Introduction

There are over 200,000 new cases diagnosed per year worldwide with skin cutaneous melanoma (SKCM), which is a very aggressive disease.1 Patients who have lived 5 years since the time of diagnosis of advanced melanoma have a 5-year over survival (OS) average of 1029%, and the total success rate of their form of chemotherapy is less than 20%.1,2 Though great efforts have been devoted to the management of advanced and metastatic SKCM, the treatment and management of it is far less effective.3 Ultraviolet radiation and hereditary predetermination are the major melanoma risk factors.4 Early detection and management of melanoma contribute to improved results as well as new treatments for even more severe stages of the disease. Mortality from melanoma has actually been remaining constant, with relatively little improvement over time, which emphasizes the significance of continuing studies on the molecular mechanisms of melanoma production and clinical goals.5

In the human body, iron is a necessary micronutrient for certain biological processes, for example, cell metabolism, cellular development, and proliferation.6 Iron homeostasis is precisely controlled by iron ingestion, systemic transport, and preservation inside the body.7 In tumor cells, alterations in iron metabolism may cause two-side impact: on the heme synthesis and sequestration, leading to the accumulation of free iron and depletion of hemoglobin.8 Although the majority of tumor cells have an elevated iron requirement, an adequate level in the body can encourage tumor growth and proliferation, iron accumulation above that range may trigger cell death, or cell death may result in membrane lipid peroxidation.9 Ferroptosis may be of use in the management of some cancers. Ferroptosis has gained popularity as a potential cancer cure after the first presentation in 2012.10 A number of experiments have concluded that ferroptosis plays a crucial function in cell death and in tumor inhibition.11 Additional studies have shown the importance of ferroptosis in diagnosis and prognosis,12 but During the formation and progression of the disease, key regulators and pathways of ferroptosis are still unclear.

The term tumor microenvironment refers to the immune cells that exist inside a tumor. TIME regulates iron synthesis and homeostasis in the body. Iron homeostasis is often maintained by Th1 cells, macrophages, etc. Further, it was discovered that immunoregulation and ferroptosis worked in concert in TIME.13 The activation of cytotoxicity in tumor cells reveals tumor antigens, enhancing the microenvironments immunogenicity and hence the treatments effectiveness and a separate research study discovered that activating CD8 T-cells can boost lipid peroxidation activity in the TIME against tumors, and the increased lipid peroxidation of the tumor cells aids the therapeutic action of immunotherapy.14,15

While there are a variety of SKCM signatures, ferroptosis studies are yet to be proven. Ferroptosis models, for the first time, are built from detailed gene expression, but representing the actual physiological status were developed for use in the SKCM population to predict the microenvironment of the patient in the patient cohort. It is possible that this approach may help with making treatment choices in the future.

A total of 460 SKCM RNA-seq data and accompanying clinical details were downloaded from TCGA database. RNA-seq data and SKCM clinical details for another 213 samples were extracted from Gene Expression Omnibus (GSE65904) database. TCGA and GEO data are freely accessible. Thus, the present study was excluded from ethics committees of the respective jurisdiction. The present study adheres to the TCGA and GEO guidelines.

For differentially expressed ferroptosis-related genes, a protein-protein interaction (PPI) network was discovered using the STRING database. For exploring the molecular interactions, the Cytoscape bioinformatics tool was used.

The search for ferroptosis-related genes of prognostic significance as part of the univariate Cox analysis of OS. By minimizing the chance of overfitting, LASSO method was used to build a predictive signature. The R package glmnet was performed for variable chosen and shrinkage. After that, multivariate regression was used to define the model with the lowest criterion score, that is goodness of fit metric.16 Afterward, the ferroptosis gene signature risk score was divided in conjunction with linear combination of the risk factor and the expression equation (). Risk score = 1 * gene1expression + 2 * gene2expression + 3 * gene3expression + + n * gene expression. Using the risk score algorithm, For each patient, a risk score was determined. To divide the patients into high-risk and low-risk categories, we used the median risk score level as a cutoff value. In this analysis, the KaplanMeier method was conducted to test the significance of variations in survival time between the high-risk and low-risk classes. The ROC curve (including 1-, 3-, and 5-year survival) was created to represent the ferroptosis-based signature using survivalROC R package to show sensitivity and specificity.

We used survival R package to complete the univariate and multivariate studies on gene signature related to ferroptosis and clinicopathologic characteristics in TCGA and GSE65904. Further, various properties were tested to determine whether the gene signature related to ferroptosis was correlated with clinicopathological factors.

In order to provide a quantitative method for predicting the survival risk for SKCM patients, the nomogram was developed by R package rms using a ferroptosis signature as well as quantitative data. In the meanwhile, calibration curves were drawn to provide an accurate estimate of predictive and test the accuracy of nomograms.

According to their calculated risk values, the SKCM samples were split into two groups (high and low risk groups). We used GSEA to differentiate between the two groups in order to discover and study the essential mechanism for KEGG pathways.17 The reference gene collection was c2.cp.kegg.v6.2.symbols.gmt, which was annotated.

In both datasets, CIBERSORT was used to measure the proportion of tumor infiltrating immune cells. Via the linear support vector principle, CIBERSORT is really effective at analyzing expression matrices of immune cell types.18 The association between 22 different types of tumor-infiltrating immune cells was investigated. An integrated study of Spearman coefficient and Wilcoxon-rank sum was performed to determine the relationship between the 22 tumor infiltrating immune cells.19 We evaluated the association between the risk score and the levels of expression levels of CTLA4, PD-1, and PD-L1, the three main immune checkpoint genes.

KaplanMeier study was performed using R packages survival and survminer. The survival package was used to analyze the Cox study. For ROC study, the R package survivalROC was used. Statistical significance is shown by a p-value < 0.05.

A total of 460 melanoma samples were obtained from the TCGA database. There were 213 individual samples from the validation dataset. Table S1 includes all the basic demographic information. Figure 1 represents the design of the present analysis.

Figure 1 Flowchart of this studys analysis protocol.

This research includes a total of 60 ferroptosis-related genes (Table S2). A PPI network was built to elucidate the interrelationships among these genes (Figure S1). We developed KaplanMeier curves from the TCGA database of ferroptosis-related genes to study OS. 10 genes were strongly related to patient outcome in the Log rank test (p < 0.05) among the 60 genes (Figure 2A). For the purpose of building a ferroptosis-related model, LASSO was applied to select the best optimal model (Figure 2B and C). 8 genes were found with the LASSO algorithms. Finally, a risk model was generated using a multivariate Cox regression analysis. The genes ALOX5 and CHAC1 have been found to be highly predictive (Figure 2D). After calculated the expression equation () The following equation is used to calculate the signatures risk value: risk score = (0.3258) x expression (ALOX5) + (0.1597) x expression (CHAC1). Among them, it was concluded that a protective effect was demonstrated for ALOX5 had coefficient <0 associated with long OS (Figure S2A). CHAC1 was associated with short OS and coefficient > 0 and considered as a high-risk factor (Figure S2B). Each patient in the TCGA and GEO cohorts was given a risk score, and they were divided into low and high risk categories.

Figure 2 The TCGA cohort was used to identify potential ferroptosis-related genes. (A) Univariate Cox regression study identifies prognostic factors. (B) LASSO coefficient distributions for the 10 ferroptosis-related possible prognostic genes. (C) Plots of the produced coefficient distributions for the logarithmic (lambda) series for parameter selection (lambda). (D) Multivariate Cox study was used to construct a ferroptosis-related gene signature in the TCGA cohort.

The risk scores were measured and the patients were divided into high- and low-risk categories based on the median level. (Figure 3A). In both TCGA and GSE65904, expression of ALOX5 was increased in conjunction with low risk, seen in heatmap (Figure 3B). The expression of CHAC1 was increased in conjunction with high risk in bot datasets. Patients in the TCGA population get a weaker OS as their risk level rises (Figure 3C). The mortality rate was also greater in the high-risk group, according to our findings (Figure 3D and E). Furthermore, for the prognostic classification of risk score, a ROC study was conducted. We looked at the prognosis prediction classification efficiency at 1, 3, and 5 years. For the survival rates of 1, 3, and 5 years in TCGA cohort, the prognostic signature had AUC values of 0.651, 0.638, and 0.622, respectively. At 1, 3, and 5 years, the AUC values in GEO dataset were 0.560, 0.636, and 0.557 (Figure 3F). Furthermore, for the prognostic classification of risk score, a ROC study was conducted. We looked at the prognosis prediction classification efficiency at 1, 3, and 5 years. For the survival rates of 1, 3, and 5 years in the TCGA cohort, the prognostic signature had AUC values of 0.651, 0.638, and 0.622, respectively. At 1, 3, and 5 years, the AUC values in the GEO dataset were 0.560, 0.636, and 0.557 (Figure 3F). These results showed that the developed prognostic tool has good sensitivity and specificity to estimate SKCM patients.We used immunohistochemistry findings from the Human Protein Atlas database to demonstrate that ALOX5 was significantly increased in normal skin tissue and CHAC1 was significantly increased in melanoma tissue to further establish the expression of two identified genes in the signature (Figure 4).

Figure 3 Ferroptosis-related gene signature has prognostic significance in SKCM both in TCGA and GEO datasets. (A) mRNA risk level distribution; (B) a heatmap of two ferroptosis-related genes in two groups from TCGA and GEO cohorts; (C) KaplanMeier study for patients classified as high or low risk based on their risk score; (D) patient survival status distribution in two groups. The dot reflects the patients condition, which is assessed as the risk score increases. (E) Mortality rates in two groups; (F) ROC curve regression in TCGA and GEO cohorts.

Figure 4 The expression of hub ferroptosis-related genes was tested using the HPA database in SKCM and normal tissue. (A) ALOX5 (B) CHAC1.

The signature models independence was determined using univariate and multivariate Cox regression analyses in clinical applications in the TCGA (Figure 5A) and GEO (Figure 5B) datasets. By using univariate Cox study, risk score was positively correlated with prognosis; however, by using multivariate Cox study, it indicated that the signature was an independent prognostic risk factor. Our results showed that the two-gene signature worked effectively in clinical practice.

Figure 5 In the TCGA and GEO cohorts, Independent prognostic factors for SKCM OS were discovered using univariate and multivariate studies. (AB) TCGA cohort (CD) GEO cohort.

We generated nomograms that combined both the ferroptosis-related signature and the typical clinicopathological factors centered on the TCGA cohort (Figure 6A) and GEO cohort (Figure 6E) to estimate OS risk of people with SKCM using a quantitative process. The nomograms had reasonable precision as an optimal model in both the TCGA dataset (Figure 6BD) and the GEO dataset, according to calibration plots (Figure 6FH).

Figure 6 (A) In the TCGA cohort, nomograms were shown to predict OS of SKCM patients based on age, stage, and risk score. (BD) TCGA cohort calibration curves after 1-, 3-, and 5 years. (E) In the GEO cohort, a nomogram dependent on stage and risk score was shown to estimate 1-, 3-, and 5-year OS of SKCM patients. (FH) GEO cohort 1-, 3-, and 5-year calibration curves.

We used GSEA to determine between high and low risk groups in terms of biological pathways. In TCGA and GEO cohorts, GSEA research showed the gene sets were greatly enriched in RNA polymerase and Aminoacyl tRNA biosynthesis. Oxidative phosphorylation was also shown to be enriched in the TCGA dataset, as was base excision repair in the GEO dataset (Figure 7).

Figure 7 GSEA enrichment between groups of low and high risk.

CIBERSORT was performed to better understand how the two-gene signature and the immune microenvironment interacted, and detailed comparisons with the risk score were created. Figure 8A shows the relative content distribution of 22 immune cells in TCGA cohort. Figure 8B shows in high-risk population, the concentrations of Macrophages M0 and Mast cells resting are higher than the other group. In the high-risk population, T cells CD4 memory resting, T cells CD8, T cells CD4 memory activated, and Macrophages M1 were lower than the other group. As seen in Figure 9, tumor-infiltrating immune cells are independent predictors of cancer survival. As a result, we evaluated whether ALOX5 expression is related to the amount of immune infiltration in SKCM. We examined the correlation between gene signatures (ALOX5 and CHAC1) and 24 immune cell subsets in SKCM and discovered that ALOX5 has a strong positive correlation with B cell memory, B cell naive, plasma cells, CD8 T cells, and T cells regulatory; however, ALOX5 has a robust negative correlation with macrophage M2, eosinophils, mast cells resting, and NK cells resting. Another analysis revealed that CHAC1 expression was substantially connected with the infiltration level of activated NK cells (R =0.15, p =0.007), T cell regulatory (R =0.11, p=0.022), and Eosinophils (R =0.11, p=0.022), but not with the infiltration level of T cell memory (R =0.21, p=0.0001).

Figure 8 Immune cell infiltration in SKCM patients: distribution and visualization (A) Description of 22 immune cell subtypes calculated compositions in TCGA. (B) In TCGA, 22 immune cell subtypes were compared between two groups.

Figure 9 Correlation between ALOX5, CHAC1 and infiltrating immune cells in SKCM patients.

The relationship between three immune checkpoint genes and risk score was studied in the TCGA and GEO cohorts. Low levels of PD-1, PD-L1, and CTLA4 demonstrated weak survival, as seen in Figure 10A. In both the TCGA and GEO datasets, we discovered the low-risk population had higher levels of PD-L1, PD-1 and CTLA4 level than high-risk group, that risk score was significantly negatively linked with CTLA4, PD-L1, and PD-1 (Figure 10BD), suggesting the low-risk group was far more likely to provide an immune response to immunotherapy.

Figure 10 The risk score and the levels of PD-1, PD-L1, and CTLA4 were linked in the TCGA and GEO cohorts. (A) KaplanMeier study for SKCM patients classified as high or low risk based on PD-1, PD-L1, and CTLA4 expression; (B) PD-1 expression in two groups and the correlation between PD-1 level and risk score; (C) PD-L1 expression in two groups and the correlation between PD-L1 level and risk score; (D) CTLA4 expression in two groups and the correlation between CTLA4 and risk score.

Melanoma is the most aggressive form of skin cancer, and its prevalence is on the increase across the world.20 While intense sporadic sun exposure is the most important risk factor for melanoma, other factors such as family background, genetic sensitivity, environmental factors, and immunosuppression often play a role.21 Since SKCM is a molecularly heterogeneous cancerous cancer, its molecular characteristics are linked to biological processes such as cell proliferation, microvascular infiltration, and distance metastasis, and they play a significant role in the prognosis of SKCM.22 As a consequence, Its critical to define important molecular markers that influence the prognosis of SKCM patients, allowing for better early diagnosis and treatment to improve SKCM clinical outcomes.

The improvement of high-throughput techniques developed has opened up the possibility of discovering new genes implicated in the onset and evolution of SKCM. Ferroptosis entails iron-dependent oxidation and is a mediated autophagic cell death process.23 Excessive intracellular iron storage is caused by disturbances in iron metabolism, which may lead to ferroptosis.24 Several genes influence ferroptosis. Previous research has shown that ferroptosis is an important method for killing SKCM cells, but the exact molecular modifications and mechanism of action remain unknown.

The aim of this research was to identify ferroptosis-related genes that were correlated with SKCM prognosis by analyzing SKCM-related RNA sequences obtained from high-throughput array technologies utilizing Cox proportional hazards regression and LASSO approaches. Previous studies identified several genes, lncRNAs and miRNAs as promising therapeutic biomarkers in SKCM.2527 However, the differentially expressed signatures were explored between the normal and tumor samples, or between the primary and metastatic tissues, and molecules associated with the progression of cancer were not taken into consideration. Our model is based on the construction of ferroptosis-related genes. We also compared the our model to other researchers such as Shou et al constructed a model based on hypoxic genes, but it did not work well in the validation set and there was no complete 1, 3 and 5 year predictive capability.28 Wu et al constructed a prediction model for SKCM, but the sample size of the validation set was too small to represent the accuracy of the model.29 Two genes (ALOX5, CHAC1) collaborated to create a prognosis model that accurately estimated the prognosis of patients with SKCM, according to our findings. Furthermore, differences in the underlying diseases of SKCM have no impact on the expression features of the two genes, meaning that the prognosis model should be used to determine prognosis in a wide range of SKCM patients. ALOX5 is a member of the arachidonic acid-derived family of proinflammatory lipid mediators. ALOX5 also plays an important role in lipid peroxidation mediation.30 ALOX5 has recently been discovered to play a key role in cell death processes such as apoptosis and ferroptosis.31 CHAC1 is a protein that belongs to the glutamylcyclotransferase family. Deglycination of the Notch receptor, which avoids receptor maturation and reduces Notch signaling, has been shown to facilitate neuronal differentiation by the encoded protein.32 This protein can also be involved in the unfolded protein reaction, glutathione control, and cellular oxidative equilibrium.33 CHAC1 was discovered to digest glutathione, converting it to 5-oxoproline and Cys-Glydipeptide, lowering intracellular GSH levels.34 Increased expression of CHAC1 in breast and ovarian cancer patients may mean a higher risk of cancer recurrence.35 Until now, the mechanism of ALOX5 and CHAC1 in SKCM has remained a mystery.

Since immune cell penetration is essential in tumors, In each SKCM specimen, CIBERSORT was also performed to measure proportional proportion of 22 different types of immune cells.36 According to some data, the interaction between the tumor and the microenvironment is important in the development of SKCM and the likelihood of responding to immunotherapies.37 As a result, we investigated whether a ferroptosis-related gene signature may be used to detect immune cell infiltration. The proportion of T cells CD4 memory resting, T cells CD8, and Macrophages M1 and T cells CD4 memory activated in low-risk group contributed more to immune response than the other group, according to our findings.

Immunotherapy has shone new light on the management of SKCM, with immune checkpoint inhibitors (ICIs) emerging as a theoretically successful treatment option.38 Anti-tumor immunity could be boosted by targeting immune checkpoint molecules.39,40 The association between ferroptosis-related gene signature and ICI reactivity was used to forecast ICI reactivity. The low-risk population had higher levels of PD-L1, PD-1, and CTLA4 expression than the high-risk category. In SKCM patients, low PD-L1, PD-1, and CTLA4 expression are linked to a weak prognosis, indicating that a ferroptosis-related gene signature has the ability to identify immunogenic and ICI-responsive SKCM patients. The therapeutic selection of ICIs in clinical practice is theoretically based on the predictive ability of ferroptosis-related gene signature. Hopefully, this predictive approach can help to speed up the development of personalized cancer immunotherapy.

Additionally, in order to evaluate the prognostic significance of the new risk model, we performed the Log rank test and the ROC curve analysis to investigate the association between the model and clinical parameters.To improve the precision of prognostic prediction, we created and validated a nomogram by combining risk score, era, and level, which could help predict clinical outcomes in SKCM patients. By the use of AUC curves, we next interrogated whether the ferroptosis-related gene patterns could serve as an early predictor for the incidence of SKCM. Our model demonstrated an AUC of 0.651, 0.638, and 0.622 in the TCGA at 1, 3, and 5 years respectively. More specifically, these modern prognostic methods have the potential to not only increase prognostic prediction precision but also to estimate the real mortality risk of particular patients, which is critical in clinical practice. Combining our prognostic model with clinicopathological indications improved prediction sensitivity and specificity for 1-, 3-, and 3-year OS, resulting in better medical therapy. To sum up, our research results indicate that a two-gene prognostic model is a reliable tool for predicting the overall survival of SKCM; it may be useful for guiding therapeutic strategies to improve the clinical outcome of melanoma patients This research has a number of advantages. First, this signature has been thoroughly tested and analyzed through a variety of databases, demonstrating its robustness and durability. Second, an extensive and in-depth study was conducted on a variety of topics, including discussions on the relationship between ferroptosis-related gene signatures and immune cells, as well as immune checkpoints. Third, a nomogram for quantitative measurement was created, which is helpful for clinical promotion and implementation. Nonetheless, there are a few flaws in our study. As a result, further SKCM patients and validations are required to validate this signature in prospective studies. However, there were several limitations to this study. Firstly, it was based solely on the TCGA and GEO databases; so, the finding must be validated using large clinical samples. Furthermore, because this study is based on a retrospective analysis, a prospective study should be conducted to confirm the model. Thirdly, more research into the processes of ALOX5, CHAC1 in SKCM is needed.

Finally, we developed a ferroptosis-based gene signature that is strongly related to the immune microenvironment and can better predict survival and represent immunotherapy efficacy in SKCM patients. The ferroptosis-related gene signature may potentially offer an important method to fulfill the therapeutic criteria of SKCM therapy to some extent in the era of precision medicine.Ferroptosis is a type of cell death that varies from apoptosis in that the formation of iron-dependent lipid peroxides causes it.41 Much or insufficient ferroptosis is associated with a rising number of physiological and pathological processes, as well as dysregulated immune responses.42 Despite being mechanistically revealed in vitro,43,44 accumulating data suggest that ferroptosis may be involved in many pathogenic scenarios.45 Ferroptosis role in T cell immunity and cancer immunotherapy, however, is uncertain.

Immune checkpoint blockade medications are novel immunotherapies that selectively activate T cells innate ability to attack tumors.46 The important function of iron in tumor development is linked to its potential to modulate both innate and acquired immune responses, particularly in T cells and macrophages. Our findings revealed a strong positive correlation between gene signatures (ALOX5 and CHAC1) and 24 immune cell subsets in SKCM, with ALOX5 having a strong positive correlation with B cell memory, B cell naive, plasma cells, CD8 T cells, and T cells regulatory; however, ALOX5 has a robust negative correlation with macrophage M2, eosinophils, mast cells resting, and NK cells resting. CHAC1 expression was found to be significantly linked to the infiltration levels of activated NK cells, T cell regulatory cells, and Eosinophils, but not to the infiltration level of T cell memory cells, according to another study.

According to a recent study showed the specific makeup of the lymphatic environment may inhibit melanoma cells from undergoing ferroptosis, therefore boosting metastasis.47 The immune systems interaction with ferroptosis is still unknown. Macrophages have a critical function in iron metabolism regulation.48 ALOX5 was found to be involved in forming leukotriene B4 (LTB4), a pro-inflammatory lipid mediator that acts as a phagocyte chemoattractant in previous investigations.49,50 Researchers also suggested that melanomas ferroptosis cells release lipid mediators such LTB4 via ALOX5 to recruit macrophages to the ferroptosis cell location. Previous research has shown that immunotherapy-activated CD8 + T cells make tumors more susceptible to ferroptosis and, as a result, improve immunotherapy efficacy in melanoma patients.51 The era of immunity and iron has dawned in cancer treatment. A potential cancer treatment is ferroptosis-driven nanotherapeutics integrated with immunomodulation.52 Immunotherapy combined with radiotherapy has been shown to trigger ferroptosis and T-cell immunity in tumors. Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.

In conclusion, we discovered two ferroptosis-related genes in the OS of SKCM with strong predictive capacity, and the prognostic model based on the two genes worked well. The ferroptosis-related gene signature may also reflect the immune microenvironment and the efficacy of immunotherapy in SKCM patients.

The authors report no conflicts of interest in this work.

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39. Khan M, Arooj S, Wang H, Cell-Based Immune NK. Checkpoint Inhibition. Front Immunol. 2020;11:167. doi:10.3389/fimmu.2020.00167

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Construction of a Ferroptosis-Related Gene Signature for Predicting Su | IJGM - Dove Medical Press

Dublin, Aug. 27, 2021 (GLOBE NEWSWIRE) -- The "Regenerative Medicine Market by Product, by Material, by Application - Global Opportunity Analysis and Industry Forecast, 2021 - 2030" report has been added to ResearchAndMarkets.com's offering.

The global regenerative medicine market is expected to reach USD 172.15 billion by 2030 from USD 13.96 billion in 2020, at a CAGR of 28.9%. Regenerative Medicine are used to regenerate, repair, replace or restore tissues and organs damaged by diseases or due to natural ageing. These medicines help in the restoration of normal cell functions and are widely used to treat various degenerative disorders such as cardiovascular disorders, orthopedic disorders and others.

The rising demand for organ transplantation and increasing awareness about the use of regenerative medicinal therapies in organ transplantation along with implementation of the 21st Century Cures Act, a U.S. law enacted by the 114th United States Congress in December 2016 are creating growth opportunities in the market. However, high cost of treatment and stringent government regulations are expected to hinder the market growth.

The global regenerative medicine market is segmented based on product type, material, application, and geography. Based on product type, the market is classified into cell therapy, gene therapy, tissue engineering, and small molecule & biologic. Depending on material, it is categorized into synthetic material, biologically derived material, genetically engineered material, and pharmaceutical. Synthetic material is further divided into biodegradable synthetic polymer, scaffold, artificial vascular graft material, and hydrogel material. Biologically derived material is further bifurcated into collagen and xenogenic material. Genetically engineered material is further segmented into deoxyribonucleic acid, transfection vector, genetically manipulated cell, three-dimensional polymer technology, transgenic, fibroblast, neural stem cell, and gene-activated matrices. Pharmaceutical is further divided into small molecule and biologic. By application, it is categorized into cardiovascular, oncology, dermatology, musculoskeletal, wound healing, ophthalmology, neurology, and others. Geographically, it is analyzed across four regions, i.e., North America, Europe, Asia-Pacific, and RoW.

The key players operating in the global regenerative medicine market include Integra Lifesciences Corporation, AbbVie Inc., Merck KGaA, Medtronic, Thermo Fisher Scientific Inc., Smith+Nephew, Becton, Dickinson and Company, Baxter International Inc, Cook Biotech, and Organogenesis Inc., among others.

Key Topics Covered:

1. Introduction

2. Regenerative Medicine Market - Executive Summary

3. Porter's Five Force Model Analysis

4. Market Overview4.1. Market Definition and Scope4.2. Market Dynamics

5. Global Regenerative Medicine Market, by Product Type5.1. Overview5.2. Cell Therapy5.3. Gene Therapy5.4. Tissue Engineering5.5. Small Molecules & Biologics

6. Global Regenerative Medicine Market, by Material6.1. Overview6.2. Synthetic Materials6.3. Biologically Derived Materials6.4. Genetically Engineered Materials6.5. Pharmaceuticals

7. Global Regenerative Medicine Market, by Application7.1. Overview7.2. Cardiovascular7.3. Oncology7.4. Dermatology7.5. Musculoskeletal7.6. Wound Healing7.7. Opthalomolgy7.8. Neurology7.9. Others

8. Global Regenerative Medicine Market, by Region8.1. Overview8.2. North America8.3. Europe8.4. Asia-Pacific8.5. Rest of World

9. Company Profile9.1. Integra Lifesciences Corporation9.2. Abbvie Inc.9.3. Merck Kgaa9.4. Medtronic plc9.5. Thermo Fisher Scientific Inc.9.6. Smith+Nephew9.7. Becton, Dickinson and Company9.8. Baxter International Inc9.9. Cook Biotech9.10. Organogenesis Inc

For more information about this report visit https://www.researchandmarkets.com/r/pl6r1p

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Worldwide Regenerative Medicine Industry to 2030 - Featuring AbbVie, Medtronic and Thermo Fisher Scientific Among Others - GlobeNewswire

Researchers at UBCs faculty of medicine and BC Cancer Research Institute have uncovered a weakness in a key enzyme that solid tumour cancer cells rely on to adapt and survive when oxygen levels are low.

The findings, published today in Science Advances, will help researchers develop new treatment strategies to limit the progression of solid cancer tumours, which represent the majority of tumour types that arise in the body.

Solid tumours rely on blood supply to deliver oxygen and nutrients to help them grow. As the tumours advance, these blood vessels are unable to provide oxygen and nutrients to every part of the tumour, which results in areas of low oxygen. Over time, this low-oxygen environment leads to a buildup of acid inside the tumour cells.

To overcome this stress, the cells adapt by unleashing enzymes that neutralize the acidic conditions of their environment, allowing the cells to not only survive, but ultimately become a more aggressive form of tumour capable of spreading to other organs. One of these enzymes is called Carbonic Anhydrase IX (CAIX).

Cancer cells depend on the CAIX enzyme to survive, which ultimately makes it their Achilles heel. By inhibiting its activity, we can effectively stop the cells from growing, explains the studys senior author Dr. Shoukat Dedhar, professor in UBC faculty of medicines department of biochemistry and molecular biology and distinguished scientist at BC Cancer.

Dr. Dedhar and colleagues previously identified a unique compound, known as SLC-0111currently being evaluated in Phase 1 clinical trialsas a powerful inhibitor of the CAIX enzyme. While pre-clinical models of breast, pancreatic and brain cancers have demonstrated the effectiveness of this compound in suppressing tumour growth and spread, other cellular properties diminish its effectiveness.

In this study, the research team, which included Dr. Shawn Chafe, a research associate in Dr. Dedhars lab, together with Dr. Franco Vizeacoumar and colleagues from the University of Saskatchewan, set out to examine these cellular properties and identify other weaknesses of the CAIX enzyme using a powerful tool known as a genome-wide synthetic lethal screen. This tool looks at the genetics of a cancer cell and systematically deletes one gene at a time to determine if a cancer cell can be killed by eliminating the CAIX enzyme together with another specific gene.

According to Dr. Dedhar, the results of their examination were surprising and point to an unexpected role of proteins and processes that control a form of cell death called ferroptosis. This form of cell death happens when iron builds up and weakens the tumours metabolism and cell membranes.

We now know that the CAIX enzyme blocks cancer cells from dying as a result of ferroptosis, says Dr. Dedhar. Combining inhibitors of CAIX, including SLC-0111, with compounds known to bring about ferroptosis results in catastrophic cell death and debilitates tumor growth.

There is currently a large international effort underway to identify drugs that can induce ferroptosis. This study is a major step forward in this quest.

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New study examines 'Achilles heel' of cancer tumours, paving the way for new treatment strategies - UBC Faculty of Medicine

WASHINGTON, July 19, 2021 /PRNewswire/ --A recently published article in Experimental Biology and Medicine (Volume 246 Issue 13, July, 2021)describes a new genetic mutation linked to hearing impairment. The study, led by Dr. Ambroise Wonkam in the Division of Human Genetics, Faculty of Health Sciences at the University of Cape Town (South Africa), reports a variant of the DMXL2 gene in Cameroonian families with hearing impairment.

The inability to hear properly in one or both ears impacts nearly 6% of the global population. Hearing impairment can be caused by environmental or genetic factors. However, establishing a definitive genetic cause can prove difficult in some cases. Approximately 70% of genetic related hearing impairment cases are non-syndromic and occur without the presence of other clinical factors. Over 120 genes have been linked to non-syndromic hearing impairment.While most cases in Europe and Asia can be traced to variants in a single gene, the GJB2 gene, the etiology of African non-syndromic hearing impairment cases is unresolved.

In this study, Dr. Wonkam and colleagues used direct sequencing methods to analyze DNA samples from a Cameroonian family with non-syndromic hearing impairment (NSHI). A mono-allelic missense variant [NM_015263.5:c.918G>T; p.(Q306H)] was identified in the DMXL2 gene in this family.This variant was present in the heterozygous state in the affected mother and the two affected children (one male and one female), and absent from the other two unaffected children (one male and one female). The variant was absent from many genome databases, over 120 control individuals from Cameroon, and 112 isolated cases of NSHI from Cameroon. This is the first report implicating DMXL2 in NSHI in Africans and confirms a previous report of this variant in China.Dr. Wonkam said, "DMXL2 is now a confirmed NSHI candidate gene in Cameroon, and more studies are needed to assess its implication in other populations around the world."

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology & Medicine, said "Dr. Wonkam and colleagues have identified a mono-allelic variant in DMLX2, also called rabconnectin-3a (RC3), in a Cameroonian family with hearing impairment. A similar variant was previously found in a Han Chinese family. It is very interesting that RC3 is found on inner ear hair cells and is a part of a synaptic vesicle protein complex involved in Ca2+-dependent neurotransmitter release in brain. Future studies aimed at a detailed understanding of the role of DMXL2 in hearing impairment is warranted."

Experimental Biology and Medicine is a global journal dedicated to the publication of multidisciplinary and interdisciplinary research in the biomedical sciences. The journal was first established in 1903. Experimental Biology and Medicine is the journal of the Society of Experimental Biology and Medicine. To learn about the benefits of society membership visit http://www.sebm.org. If you are interested in publishing in the journal, please visit http://ebm.sagepub.com.

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Advances in the Genetic Etiology of Hearing Impairment - PRNewswire

What happened

Companies associated with gene-editing are near the end of their second poor week in a row on Wall Street. For the week, shares of CRISPR Therapeutics (NASDAQ:CRSP) were down by 12% as of Thursday's market close. Editas Medicine (NASDAQ:EDIT) was off by about 14% over those four days, and Beam Therapeutics (NASDAQ:BEAM) had lost 15%.

Those downward moves came on the heels of a huge June run-up after Intellia Therapeutics (NASDAQ:NTLA) -- another gene-editing company -- announced that its approach had successfully reversed a genetic disease in human patients. In a clinical trial first, researchers injected a CRISPR treatment into patients that effectively inactivated the body's production of a mutated (and eventually toxic) form of a protein by altering the patients' DNA. Intellia and its partner Regeneron will now navigate the standard regulatory review process. Intellia CEO John Leonard has said he hopes the therapy becomes available to patients "very, very soon." However, marketability could still be years away. Meanwhile, Wall Street's recent surge of excitement about CRISPR therapies has worn off.

BEAM data by YCharts

The drops are notable as investors initially saw this breakthrough result as a positive for all gene-editing stocks. CRISPR Therapeutics, Editas, and Intellia are all taking similar approaches to editing genes -- using the CRISPR-Cas9 enzyme, which functions like a scissors. Beam Therapeutics, on the other hand, uses base-editing, an approach that alters DNA more like a pencil and eraser. Nearly three weeks removed from Intellia's announcement, the market has clearly decided its breakthrough is much more company-specific.

Image source: Getty Images.

It appears gene-editing investors who don't hold Intellia will have to wait for their own companies' catalysts to see big gains. Of these three, CRISPR Therapeutics is the one whose lead candidate is furthest along in clinical trials. CRISPR and its partner, Vertex Pharmaceuticals, have dosed more than 40 patients in a trial studying CTX001 in patients with sickle cell and beta-thalassemia. All patients at least three months removed from the procedure have shown a consistent and positive response to CTX001. Every previously transfusion-dependent patient in the trial has become transfusion-free since receiving the one-time treatment.

CTX001 is currently in a phase 1/2 study, and CRISPR Therapeutics hasn't offered any estimates about when it anticipates that it could be commercially available. But it recently signed an agreement with a smaller startup, Capsida Biotherapeutics, to develop an in vivo therapy for two diseases -- amyotrophic lateral sclerosis (ALS) and Friedreich's ataxia.

Editas has both in vivo and ex vivo (gene-editing done outside the body) candidates in early-stage clinical trials. Its in vivo candidate, EDIT-101, is a treatment for the most common form of childhood blindness. For this program, management has a meeting scheduled with the independent data monitoring committee this summer, and plans to share clinical data by the end of the year.

The company's also developing an ex vivo treatment for sickle cell disease that takes a slightly different approach than the one being used by other gene-editing companies. Editas is using the Cas12a enzyme instead of the more commonly used Cas9. The Cas12a approach has shown better editing efficiency in some studies and only requires one RNA molecule for editing as opposed to Cas9, which requires two.

For now, Beam Therapeutics is furthest back on the research and development path. Its programs are in preclinical stages. Its most advanced candidate also targets sickle cell disease and beta-thalassemia.

Investors' excitement about Beam has been less about its individual treatments and more about the gene-editing technology the company is using. Its base-editing approach could offer a more precise and predictable tool to modify DNA for treating diseases. The company hopes that will allow it to effectively leapfrog its rivals in the next few years. Management has predicted it will file with the FDA for an investigational new drug (IND) designation for its lead candidate later this year. Receiving that designation will give it the green light to test the treatment in humans trials. It also plans to move two more programs into the IND-enabling stage.

This article represents the opinion of the writer, who may disagree with the official recommendation position of a Motley Fool premium advisory service. Were motley! Questioning an investing thesis -- even one of our own -- helps us all think critically about investing and make decisions that help us become smarter, happier, and richer.

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Why CRISPR Therapeutics, Editas Medicine, and Beam Therapeutics Dropped This Week - The Motley Fool

Media Advisory

Friday, July 16, 2021

Results provide hope for children with aromatic L-amino acid decarboxylase deficiency.

A new study published in Nature Communications suggests that gene therapy delivered into the brain may be safe and effective in treating aromatic L-amino acid decarboxylase (AADC) deficiency. AADC deficiency is a rare neurological disorder that develops in infancy and leads to near absent levels of certain brain chemicals, serotonin and dopamine, that are critical for movement, behavior, and sleep. Children with the disorder have severe developmental, mood dysfunction including irritability, and motor disabilities including problems with talking and walking as well as sleep disturbances. Worldwide there have been approximately 135 cases of this disease reported.

In the study, led by Krystof Bankiewicz, M.D., Ph.D., professor of neurological surgery at Ohio State College of Medicine in Columbus, and his colleagues, seven children received infusions of the DDC gene that was packaged in an adenovirus for delivery into brain cells. The DDC gene is incorporated into the cells DNA and provides instructions for the cell to make AADC, the enzyme that is necessary to produce serotonin and dopamine. The research team used magnetic resonance imaging to guide the accurate placement of the gene therapy into two specific areas of the midbrain.

Positron emission tomography (PET) scans performed three and 24 months after the surgery revealed that the gene therapy led to the production of dopamine in the deep brain structures involved in motor control. In addition, levels of a dopamine metabolite significantly increased in the spinal fluid.

The therapy resulted in clinical improvement of symptoms. Oculogyric crises, abnormal upward movements of the eyeballs, often with involuntary movements of the head, neck and body, that can last for hours and are a hallmark of the disease, completely went away in 6 of 7 participants. In some of the children, improvement was seen as early as nine days after treatment. One participant continued to experience oculogyric crises, but they were less frequent and severe.

All of the children exhibited improvements in movement and motor function. Following the surgery, parents of a majority of participants reported their children were sleeping better and mood disturbances, including irritability, had improved. Progress was also observed in feeding behavior, the ability to sit independently, and in speaking. Two of the children were able to walk with support within 18 months after receiving the gene therapy.

The gene therapy was well tolerated by all participants and no adverse side effects were reported. At three to four weeks following surgery, all participants exhibited irritability, sleep problems, and involuntary movements, but those effects were temporary. One of the children died unexpectedly seven months after the surgery. The cause of death was unknown but assessed to be due to the underlying primary disease.

Jill Morris, Ph.D., program director, NIHs National Institute of Neurological Disorders and Stroke (NINDS). To arrange an interview, please contact nindspressteam@ninds.nih.gov

Pearson TS et al., Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons, Nature Communications, July 12, 2021. https://doi.org/10.1038/s41467-021-24524-8

This study was supported by NINDS (R01NS094292, NS073514-01).

The NINDS NINDS is the nations leading funder of research on the brain and nervous system.The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

###

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funded study finds gene therapy may restore missing enzyme in rare disease - National Institutes of Health

When she isnt pursuing her favorite heart-pumping activities of running, swimming, or cycling, Sharlene M. Day, a presidential associate professor of cardiovascular medicine and director of Translational Research for the Penn Cardiovascular Institute, is focused on the heart in another way; trying to unlock and treat the mysteries of genetic heart disease.

As part of her research at the Day Lab, Day integrates translational and clinical science to understand the full spectrum of genetic heart disease evolution and progression, from gene mutations in heart muscle cells to ways of predicting negative outcomes in patients. Clinically, she sees patients with hypertrophic cardiomyopathy, a condition where the heart muscle becomes thick making it harder for blood to leave the heart, and other genetic heart conditions at the Penn Center for Inherited Cardiac Disease, such as inherited arrhythmias, high blood cholesterol, Marfan syndrome and familial amyloidosis. Her research program primarily focuses on these same conditions.

A physician scientist, Day completed her residency, followed by a cardiology fellowship, and a postdoctoral research fellowship at the University of Michigan before joining the faculty there, and spent 24 years there before coming to Penn. Day was recruited to Penn Medicine to lead initiatives in translational research within the Cardiovascular Institute and to grow the clinical and academic mission in the Penn Center for Inherited Cardiovascular Disease.

Very early on in my training, I became fascinated with the interplay between genetics and cardiac physiology that manifest in very unique observable cardiac traits and complicated disease trajectories including both heart failure and arrhythmias, also known as irregular heartbeats, says Day.

This story is by Sophie Kluthe. Read more at Penn Medicine News.

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Getting to the heart of genetic cardiovascular diseases | Penn Today - Penn Today

MIAMI--(BUSINESS WIRE)--Organicell Regenerative Medicine, Inc. (OTCMKTS: BPSR), a clinical-stage biopharmaceutical company dedicated to the development of regenerative therapies, today announced that the Company will be presenting at the annual meeting of the International Society of Cell and Gene Therapy (ISCT) taking place on May 26-28, 2021.

Organicells work, which was selected for an oral presentation, will be part of a session titled: "EVs for Infectious Diseases and Preparedness for Future Pandemics - ISCT-ISEV Joint Session and is scheduled to be broadcast live to program registrants on May 27th.

This presentation comes as a follow up to recently published case report studies demonstrating the investigation of Zofin in three severely ill COVID-19 patients. In these studies, results found the administration of Zofin to be associated with decreased levels of inflammatory biomarkers, such as CRP and IL6.

COVID-19 infection complications are, in part, the result of an excessive immune response with the over-production of pro-inflammatory cytokines such as IL6 and CRP. Therefore, the observation of reduced concentration of these biomarkers may indicate a positive trend towards recovery.

ISCT is the global steward fostering cell and gene therapy translation to the clinic. With a network of leading clinicians, regulators, researchers, technologists and industry partners, ISCT members have a shared vision to translate cell and gene therapies into safe and effective therapies to improve patients lives worldwide. For more information about the organization, please visit: isctglobal.org.

We are excited that our work was selected amongst other researchers investigating the therapeutic potential of extracellular vesicles for infectious disease of future pandemics, said Mari Mitrani, M.D., Ph.D., Chief Science Officer of Organicell.

About Zofin:

Zofin is an acellular biologic therapeutic derived from perinatal sources and is manufactured to retain naturally occurring microRNAs, without the addition or combination of any other substance or diluent. This product contains over 300 growth factors, cytokines, and chemokines as well as other extracellular vesicles/nanoparticles derived from perinatal tissues. Zofin is currently being tested in a phase I/II randomized, double blinded, placebo trial to evaluate the safety and potential efficacy of intravenous infusion of Zofin for the treatment of moderate to SARS related to COVID-19 infection vs placebo.

ABOUT ORGANICELL REGENERATIVE MEDICINE, INC.

Organicell Regenerative Medicine, Inc. (OTCMKTS: BPSR) is a clinical-stage biopharmaceutical company that harnesses the power of exosomes to develop innovative biological therapeutics for the treatment of degenerative diseases. The Companys proprietary products are derived from perinatal sources and manufactured to retain the naturally occurring exosomes, hyaluronic acid, and proteins without the addition or combination of any other substance or diluent. Based in South Florida, the company was founded in 2008 by Albert Mitrani, Chief Executive Officer and Dr. Mari Mitrani, Chief Scientific Officer. To learn more, please visit https://organicell.com/.

FORWARD-LOOKING STATEMENTS

Certain of the statements contained in this press release should be considered forward-looking statements within the meaning of the Securities Act of 1933, as amended (the Securities Act), the Securities Exchange Act of 1934, as amended (the Exchange Act), and the Private Securities Litigation Reform Act of 1995. These forward-looking statements are often identified by the use of forward-looking terminology such as will, believes, expects, potential or similar expressions, involving known and unknown risks and uncertainties. Although the Company believes that the expectations reflected in these forward-looking statements are reasonable, they do involve assumptions, risks and uncertainties, and these expectations may prove to be incorrect. We remind you that actual results could vary dramatically as a result of known and unknown risks and uncertainties, including but not limited to: potential issues related to our financial condition, competition, the ability to retain key personnel, product safety, efficacy and acceptance, the commercial success of any new products or technologies, success of clinical programs, ability to retain key customers, our inability to expand sales and distribution channels, legislation or regulations affecting our operations including product pricing, reimbursement or access, the ability to protect our patents and other intellectual property both domestically and internationally and other known and unknown risks and uncertainties, including the risk factors discussed in the Companys periodic reports that are filed with the SEC and available on the SECs website (http://www.sec.gov). You are cautioned not to place undue reliance on these forward-looking statements All forward-looking statements attributable to the Company or persons acting on its behalf are expressly qualified in their entirety by these risk factors. Specific information included in this press release may change over time and may or may not be accurate after the date of the release. Organicell has no intention and specifically disclaims any duty to update the information in this press release.

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Organicell To Present Results Of Zofin Clinical Studies At The International Society Of Cell And Gene Therapy Annual Meeting - Business Wire

SAN RAFAEL, Calif., July 19, 2021 /PRNewswire/ --BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) today announced new data for valoctocogene roxaparvovec, an investigational gene therapy for the treatment of adults with severe hemophilia A, in its positive pivotal study, GENEr8-1, during an oral presentation at the International Society on Thrombosis and Haemostasis (ISTH) 2021 Virtual Congress. The pivotal study demonstrated superiority to Factor VIII prophylaxis in key clinical efficacy endpoints. With 134 participants, this is the largest global Phase 3 study to date for gene therapy in hemophilia. All participants in the study received a single dose of valoctocogene roxaparvovec and completed a year or more of follow-up. Top-line one-year results from this study were previously communicated in January 2021.

New data presented at ISTH include more details on annualized bleeding rate (ABR) in all study participants and annualized Factor VIII utilization rate, in terms of international units per kilogram per year (IU/kg/year) of replacement Factor VIII. Over 90 percent (N=134) of all participants in the GENEr8-1 study had an annualized bleed rate (ABR) of zero or a lower bleed rate than baseline after week 4 after treatment with valoctocogene roxaparvovec.

New data presented at ISTH also include information on Factor VIII utilization after treatment with valoctocogene roxaparvovec. Mean annualized Factor VIII utilization rate, among a pre-specified group of prior participants in a non-interventional baseline observational study (rollover population; N=112) decreased from baseline on Factor VIII prophylaxis by 99% from 3961.2 (median 3754.4) to 56.9 (median 0) IU/kg/year after week 4 after treatment with valoctocogene roxaparvovec (p-value <0.001).

As previously shared in January 2021, data from the pre-specifiedrollover population(N=112)in the GENEr8-1 study with a mean follow-up of 71.6 weeks demonstrated that in the pre-specified primary analysis for ABR, calculated through each subject's last assessment, a single dose of valoctocogene roxaparvovec significantly reduced mean ABR by 84% from a prospectively collected 4.8 (median 2.8) at baseline to 0.8 (median 0.0) bleeding episodes per year (p-value <0.001).

In addition, the mean annualized Factor VIII infusion rate was reduced by 99% from 135.9 (median 128.6) to 2.0 (median 0.0) infusions per year (p-value <0.001).

Table 1: Mean/Median Annualized Bleeding Rate (ABR) and FVIII Infusion Rate in Phase 3 GENEr8-1 Study Rollover Population (N=112) after Week 4 Through Week 52 at November 2020 Cut Off

Phase 3

Rollover Population*

On Factor VIII prophylaxis, before valoctocogene roxaparvovec infusion

N=112

Phase 3

Rollover Population*

After valoctocogene roxaparvovec infusion

N=112

Mean (SD)

Median (IQR)

Mean (SD)

Median (IQR)

Annualized Bleeding Rate (bleeding episodes per year)

4.8 (6.5)

2.8 (0.0, 7.6)

0.8 (3.0)

0.0 (0.0, 0.0)

Annualized FVIIIUtilizationRate(IU per kgper year)

3961.2 (1751.5)

3754.4(2799.5, 4706.8)

56.9 (194.6)

0.0 (0.0,22.1)

Annualized FVIII Infusion Rate (infusions per year)

135.9 (52.0)

128.6 (104.1, 159.9)

2.0 (6.4)

0.0 (0.0, 0.9)

*See study description for patient population information.

Study participants also experienced a clinically meaningful increase in endogenous Factor VIII expression. At the end of the first year post-infusion with valoctocogene roxaparvovec, participants in the modified intent-to-treat (mITT) population (N=132) had a significant increase in mean endogenous Factor VIII expression level from an imputed baseline of 1 IU/dL to 42.9 IU/dL (median 23.9) (p-value <0.001) as measured by the chromogenic substrate (CS) assay, supporting the marked clinical benefits observed with abrogation of bleeding episodes and Factor VIII utilization and infusion rates. In a subset of the mITT population that had been dosed at least two years prior to the data cut date (N=17), Factor VIII expression declined from a mean of 42.2(median 23.9) IU/dL at the end of year one to 24.4 (median 14.7) IU/dL at the end of year two with continued hemostatic efficacy.

Table 2: Factor VIII Activity Levels in 12-Month Intervals

Median Factor VIII Activity, IU/dL

Phase 3 mITT Population*

(N=132)

Mean (SD)

Median

Phase 3 mITT Subset Population**

(N=17)

Mean (SD)

Median

Week 52

42.9 (45.5)

23.9 (11.9, 62.3)

42.2 (50.9)

23.9 (11.2, 55.0

Week 104

N/A

24.4 (29.2)

14.7 (6.4, 28.6)

*mITT= modified intent-to-treatpopulation, whichexcludes 2 HIV- positive subjects dosed 2 or more years prior to November 2020 data cut.

**Includes only HIV-negative subjects dosed 2 or more years prior to Nov 2020 data cut date. One participant was lost to follow-up at 66.1 weeks and was henceforth imputed to have a Factor VIII activity of 0 IU/dL through 104 weeks.

"The demonstrated bleed control at 52 weeks and beyond in this pivotal study supports our thesis that gene therapy can play an important role in the treatment of severe hemophilia A and potentially creates the possibility for a new treatment paradigm," said Margareth C. Ozelo, MD, PhD, Director, INCT do SangueHemocentroUNICAMP,University of Campinas and Lead Principal Investigator of the GENEr8-1 Study. "It is encouraging to see meaningful endogenous Factor VIII expression and decreases in bleeding and Factor VIII infusions for people in this study. These pivotal results contribute to the growing body of data to increase understanding of the safety and efficacy of gene therapy treatment over time."

"From the start of our valoctocogene roxaparvovec program, our goal remains to advance treatment options for people with severe hemophilia A in light of the unmet need in bleed control. Current prophylactic therapies for hemophilia A cannot maintain Factor VIII levels for sustained periods, leading to the need for frequent, regular infusions or injections while still having a risk of ongoing, unpredictable bleeds and unavoidable, irreversible joint damage even with standard of care treatment," said Hank Fuchs, M.D., President of Worldwide Research and Development at BioMarin. "These data build upon the foundation for a potential transformative treatment option that addresses the root cause of severe hemophilia A. Later at ISTH, we look forward to sharing five years of clinical data from the ongoing Phase 1/2 study with the longest duration of clinical experience, which complements this pivotal Phase 3 study, the largest study of a gene therapy in hemophilia A."

Valoctocogene Roxaparvovec Safety

Overall, in the Phase 3 study, valoctocogene roxaparvovec has been welltolerated by the 134participants who received a single 6e13 vg/kg dose. No participants withdrew due to adverse events. No participants developed inhibitors to Factor VIII, or experienced thromboembolic events. One participant was lost to follow-up. Infusion reactions were defined as any AEs occurring within 48 hours post-infusion. The most common infusion reactions were nausea (14.2%), fatigue (7.5%), and headache (6.0%). Systemic hypersensitivity during or following infusion was mitigated by slowing or pausing infusion and treating with supportive medications, as indicated. All four (3.0%) participants with an interruption due to infusion-related symptoms were able to complete their infusion. Twenty-two (16.4%) participants experienced a total of 43 serious adverse events (SAEs), and all SAEs resolved.

Common, steroid-related side effects can occur with temporary use of corticosteroid (or alternative immunosuppressants) to manage ALT elevation. ALT elevation was the most common AE. Overall, 79% of participants received corticosteroids per protocol as treatment for ALT elevation. The average duration of corticosteroid treatment was 33 weeks. Overall, 72% of participants who used any corticosteroidsreported AEs attributed to their use, most commonly acne, insomnia, cushingoid changes, and weight increased. Three participants reported SAEs attributed to corticosteroids. Other immunosuppressants were used by 29% of participants for ALT elevation due to contraindication, side effects, or poor or no response to corticosteroid treatment. No Grade 4 ALT elevations occurred, and no participants met Hy's law criteria for drug-induced liver injury.

GENEr8-1 Study Description

The global Phase 3 GENEr8-1 study evaluates superiority of valoctocogene roxaparvovec at the 6e13 vg/kg dose compared to FVIII prophylactic therapy. All study participants had severe hemophilia A at baseline, defined as less than or equal to 1 IU/dL of Factor VIII activity. The study included 134 total participants, all of whom had a minimum of 12 months of follow-up at the time of the data cut. The first 22 participants were directly enrolled into the Phase 3 study, 17 of whom were HIV-negative and dosed at least 2 years prior to the data cut date (referred to as the subset). The remaining 112 participants (rollover population) completed at least six months in a separate non-interventional study to prospectively assess bleeding episodes, Factor VIII use, and health-related quality of life while receiving Factor VIII prophylaxis prior to rolling over to receive a single infusion of valoctocogene roxaparvovec in the GENEr8-1 study.

Regulatory Status

The European Medicines Agency (EMA) validated BioMarin's resubmission of a Marketing Authorization Application (MAA) on July 15, 2021. In May 2021, the EMA granted the Company's request for accelerated assessment. Accelerated assessment potentially reduces the time frame for the EMA Committee for Medicinal Products for Human Use (CHMP) and Committee for Advanced Therapies (CAT) to review a MAA for an Advanced Therapy Medicinal Product (ATMP), although an application initially designated for accelerated assessment can revert to the standard procedure during the review for a variety of reasons.The decision to grant accelerated assessment has no impact on the eventual CHMP and CAT opinion on whether a marketing authorization should be granted. A CHMP and CAT opinion is anticipated in the first half of 2022.

The MAA submission includes safety and efficacy data from the 134 subjects enrolled in the Phase 3 GENEr8-1 study, all of whom have been followed for at least one year after treatment with valoctocogene roxaparvovec, as well as four and three years of follow-up from the 6e13 vg/kg and 4e13 vg/kg dose cohorts, respectively, in the ongoing Phase 1/2 dose escalation study.

In the United States, BioMarin intends to submit two-year follow-up safety and efficacy data on all study participants from the Phase 3 GENEr8-1 study to support the benefit/risk assessment of valoctocogene roxaparvovec, as previously requested by the Food and Drug Administration (FDA). BioMarin is targeting a Biologics License Application (BLA) resubmission in the second quarter of 2022, assuming favorable study results, followed by an expected six-month review by the FDA.

The FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation to valoctocogene roxaparvovec inMarch 2021. RMAT is an expedited program intended to facilitate development and review of regenerative medicine therapies, such as valoctocogene roxaparvovec, that are intended to address an unmet medical need in patients with serious conditions. The RMAT designation is complementary to Breakthrough Therapy Designation, which the Company received in 2017.

In addition to the RMAT Designation and Breakthrough Therapy Designation, BioMarin's valoctocogene roxaparvovec also has received orphan drug designation from the FDA and EMA for the treatment of severe hemophilia A.The Orphan Drug Designation program is intended to advance the evaluation and development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.

Robust Clinical Program

BioMarin has multiple clinical studies underway in its comprehensive gene therapy program for the treatment of hemophilia A. In addition to the global Phase 3 study GENEr8-1 and the ongoing Phase 1/2 dose escalation study, the Company is actively enrolling participants in a Phase 3b, single arm, open-label study to evaluate the efficacy and safety of valoctocogene roxaparvovec at a dose of 6e13 vg/kg with prophylactic corticosteroids in people with hemophilia A. The Company is also running a Phase 1/2 Study with the 6e13 vg/kg dose of valoctocogene roxaparvovec in people with hemophilia A with pre-existing AAV5 antibodies, as well as another Phase 1/2 Study with the 6e13 vg/kg dose of valoctocogene roxaparvovec in people with hemophilia A with active or prior FVIII inhibitors.

About Hemophilia A

People living with hemophilia A lack sufficient functioning Factor VIII protein to help their blood clot and are at risk for painful and/or potentially life-threatening bleeds from even modest injuries. Additionally, people with the most severe form of hemophilia A (FVIII levels <1%) often experience painful, spontaneous bleeds into their muscles or joints. Individuals with the most severe form of hemophilia A make up approximately 45 to 50 percent of the hemophilia A population. People with hemophilia A with moderate (FVIII 1-5%) or mild (FVIII 5-40%) disease show a much-reduced propensity to bleed. The standard of care for adults with severe hemophilia A is a prophylactic regimen of replacement Factor VIII infusions administered intravenously up to two to three times per week or 100 to 150 infusions per year. Despite these regimens, many people continue to experience breakthrough bleeds, resulting in progressive and debilitating joint damage, which can have a major impact on their quality of life.

Hemophilia A, also called Factor VIII deficiency or classic hemophilia, is an X-linked genetic disorder caused by missing or defective Factor VIII, a clotting protein. Although it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a new mutation that was not inherited. Approximately 1 in 10,000 people have Hemophilia A.

About ISTH

Founded in 1969, the ISTH is the leading worldwide not-for-profit organization dedicated to advancing the understanding, prevention, diagnosis and treatment of thrombotic and bleeding disorders. The ISTH is an international professional membership organization with more than 7,700 clinicians, researchers and educators working together to improve the lives of patients in more than 110 countries around the world. Among its highly regarded activities and initiatives are education and standardization programs, research activities, meetings and congresses, peer-reviewed publications, expert committees and World Thrombosis Day on 13 October.

About BioMarin

BioMarin is a global biotechnology company that develops and commercializes innovative therapies for serious and life-threatening rare and ultra-rare genetic diseases. The Company's portfolio consists of six commercialized products and multiple clinical and pre-clinical product candidates. For additional information, please visitwww.biomarin.com. Information on BioMarin's website is not incorporated by reference into this press release.

Forward-Looking Statements

This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including without limitation, statements about (i) the development of BioMarin's valoctocogene roxaparvovec program generally, (ii) the anticipated timing of a CHMP and CAT opinion in the first half of 2022, (iii) BioMarin's intention to submit to the U.S. Food and Drug Administration (FDA) two-year follow-up safety and efficacy data on all study participants from the GENEr8-1 study to support the benefit/risk assessment of valoctocogene roxaparvovec, (iv) BioMarin targeting resubmission of a Biologics License Application in the second quarter of 2022 assuming favorable study results, followed by an expected six-month review procedure by the FDA, (v) the anticipated Phase 1/2 study to be presented later at ISTH and (vi) the timing of the regulatory activities in the U.S andEurope, including validation and timing of potential approvals and the expected review procedures. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements. These risks and uncertainties include, among others: results and timing of current and planned preclinical studies and clinical trials of valoctocogene roxaparvovec, including final analysis of the above data and additional data from the continuation of these trials; any potential adverse events observed in the continuing monitoring of the patients in the clinical trials; the content and timing of decisions by the FDA, the EMA and other regulatory authorities; the content and timing of decisionsby local and central ethics committees regarding the clinical trials; our ability to successfully manufacture valoctocogene roxaparvovec for the clinical trials and commercially, if approved; and those other risks detailed from time to time under the caption "Risk Factors" and elsewhere in BioMarin's Securities and Exchange Commission (SEC) filings, including BioMarin's Quarterly Report on Form 10-Q for the quarter endedMarch 31, 2021, and future filings and reports by BioMarin... BioMarin undertakes no duty or obligation to update any forward-looking statements contained in this press release as a result of new information, future events or changes in its expectations.

BioMarin is a registered trademark of BioMarin Pharmaceutical Inc.

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BioMarin Announces Oral Presentation of Positive One-Year Results from Phase 3 Pivotal Trial with Valoctocogene Roxaparvovec Gene Therapy in Adults...

Editors note: A recording of the conversation is embedded below.

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CAMBRIDGE, Mass. & FARGO, N.D.--(BUSINESS WIRE)--Moderna, Inc. (Nasdaq:MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, and Aldevron, LLC, the leading provider of high-quality plasmid DNA, mRNA and recombinant proteins necessary for vaccines, gene and cell therapy, gene editing and diagnostic applications, have announced their expanded collaboration in support of the Moderna COVID-19 Vaccine and additional programs in Modernas clinical development pipeline.

Specifically, Aldevron will supply plasmid DNA to serve as the genetic template for generating the COVID-19 mRNA vaccine and other investigational programs in Modernas pipeline.

Aldevron has been a long-standing partner of Moderna. We appreciate their collaboration and their expertise in the biologics space, said Juan Andres, Chief Technical Operations and Quality Officer of Moderna. We look forward to our ongoing work with this expanded partnership.

Aldevrons support of the Moderna pipeline spans nearly a decade, and were incredibly proud of the trust theyve placed in us commented Kevin Ballinger, Chief Executive Officer of Aldevron. Our deep experience, coupled with enhanced operational efficiencies and recent capacity expansion place us in an excellent position to support Modernas efforts especially during this critical time. We look forward to expanding our strategic partnership to serve a pipeline of important new programs in the future.

Aldevrons production of DNA continues to take place in its 70,000 sq ft GMP facility located in Fargo, North Dakota. Buildout and validation of an additional 189,000 sq ft expansion to the GMP facility on Aldevrons 14-acre Breakthrough Campus has been completed, enabling additional manufacturing capacity.

About Aldevron

Aldevron is a premier manufacturing partner in the global genetic medicine field. Founded in 1998 by Michael Chambers and John Ballantyne, the company provides critical nucleic acids and proteins used to make gene and cell therapies, DNA and RNA vaccines, and gene editing technologies. Aldevrons 600 employees support thousands of scientists who are developing revolutionary treatments for millions of people.

About Moderna

In 10 years since its inception, Moderna has transformed from a science research-stage company advancing programs in the field of messenger RNA (mRNA), to an enterprise with a diverse clinical portfolio of vaccines and therapeutics across six modalities, a broad intellectual property portfolio in areas including mRNA and lipid nanoparticle formulation, and an integrated manufacturing plant that allows for both clinical and commercial production at scale and at unprecedented speed. Moderna maintains alliances with a broad range of domestic and overseas government and commercial collaborators, which has allowed for the pursuit of both groundbreaking science and rapid scaling of manufacturing. Most recently, Modernas capabilities have come together to allow the authorized use of one of the earliest and most-effective vaccines against the COVID-19 pandemic.

Modernas mRNA platform builds on continuous advances in basic and applied mRNA science, delivery technology and manufacturing, and has allowed the development of therapeutics and vaccines for infectious diseases, immuno-oncology, rare diseases, cardiovascular diseases and auto-immune diseases. Today, 24 development programs are underway across these therapeutic areas, with 14 programs having entered the clinic. Moderna has been named a top biopharmaceutical employer by Science for the past six years. To learn more, visit http://www.modernatx.com.

Modernas Forward Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including regarding: the supply by Aldevron of plasmid DNA for Moderna products, including the Companys COVID-19 vaccine. In some cases, forward-looking statements can be identified by terminology such as will, may, should, could, expects, intends, plans, aims, anticipates, believes, estimates, predicts, potential, continue, or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this press release are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties, and other factors, many of which are beyond Modernas control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. These risks, uncertainties, and other factors include, among others: the fact that there has never been a commercial product utilizing mRNA technology approved for use; the fact that the rapid response technology in use by Moderna is still being developed and implemented; the safety, tolerability and efficacy profile of the Moderna COVID-19 Vaccine observed to date may change adversely in ongoing analyses of trial data or subsequent to commercialization; despite having ongoing interactions with the FDA or other regulatory agencies, the FDA or such other regulatory agencies may not agree with Modernas regulatory approval strategies, components of our filings, such as clinical trial designs, conduct and methodologies, or the sufficiency of data submitted; Moderna may encounter delays in meeting manufacturing or supply timelines or disruptions in its distribution plans for the Moderna COVID-19 Vaccine; whether and when any biologics license applications and/or emergency use authorization applications may be filed and ultimately approved by regulatory authorities; potential adverse impacts due to the global COVID-19 pandemic such as delays in regulatory review, manufacturing and clinical trials, supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy; and those other risks and uncertainties described under the heading Risk Factors in Modernas most recent Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (SEC) and in subsequent filings made by Moderna with the SEC, which are available on the SECs website at http://www.sec.gov. Except as required by law, Moderna disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release in the event of new information, future developments or otherwise. These forward-looking statements are based on Modernas current expectations and speak only as of the date hereof.

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Moderna and Aldevron Announce Expanded Partnership for mRNA Vaccine and Therapeutic Pipeline - Business Wire

Alliance for Regenerative Medicine, European Federation of Pharmaceutical Industries and Associations, and European Association for Bioindustries Call for Advanced Therapies to be Exempt from EU GMO Legislation

COVID-19 highlights how the EU can adapt legislation to meet urgent health needs

A permanent exemption would help to accelerate access to life-changing medicines for European patients

BRUSSELS, BELGIUM May 25, 2021

The European Commission should exempt advanced therapies from Genetically Modified Organism (GMO) legislation, which hurts Europes ability to attract clinical trials and delays patient access to transformative medicines, said the Alliance for Regenerative Medicine (ARM), the European Federation of Pharmaceutical Industries and Associations (EFPIA), and the European Association of Bioindustries (EuropaBio) in a paper published online yesterday in the journal Human Gene Therapy.

The European Commission recognized that GMO requirements hinder the conduct of clinical trials in its April 29 study on new genomic techniques and in the 2020 Pharmaceutical Strategy for Europe, when it called for GMO legislation to be fit for purpose for addressing medicines. The original GMO legislation was primarily enacted to protect food consumers and the environment, but Advanced Therapy Medicinal Products (ATMPs) such as gene therapies are affected as an unintended consequence. The uneven application of GMO requirements across EU Member States causes significant clinical trial delays despite findings that gene therapies pose a negligible risk to the environment.

Galvanized by the pandemic, the European Commission granted a temporary derogation from GMO requirements to investigational COVID-19 medicinal products to accelerate the development of vaccines and treatments. An industry survey suggested that the temporary derogation decreased the amount of time required to complete clinical trials in Europe. A similar, but permanent, exemption is justified for gene therapies -- which often treat life-threatening diseases that have few, or no, treatment options while still preserving high quality and safety standards.

The European Commission recognised that time was of the essence when lifting GMO requirements for COVID-19 vaccines and treatments, said Paige Bischoff, ARMs Senior Vice President of Global Public Affairs. Time is also very much of the essence for people with cancer, inherited disorders and other life-threatening conditions. We call on the European Commission to take the same measures for advanced therapies and remove the unnecessary and unintended burden of GMO legislation so patients have timely access to transformative, potentially curative medicines.

The organisations call on the European Commission to put forward a proposal by 2022, the timeframe proposed by the Pharmaceutical Strategy for Europe. Without an exemption for gene therapies, the GMO requirements threaten the regions competitiveness with other parts of the world where GMO legislation is less complex and cumbersome. A 2019 ARM report, for example, found that the number of ATMP clinical trials in Europe stayed roughly flat over a four-year period (2014-2018) while increasing substantially in North America (+36%) and in Asia (+28%). Europe is at risk of falling further behind: At the end of 2020 the ATMP sector was conducting 1,220 clinical trials worldwide, up from 1,066 in 2019.

"In 2020, we welcomed the derogation from GMO legislation for COVID-19 treatments or vaccines in clinical trials, said Pr Tellner,Director of Regulatory Affairs at EFPIA. Member companies are increasingly reporting how the derogation has removed the significant and time-consuming hurdles associated with GMO submissions, in addition to the clinical trial application. Swift action to a permanent exemption from GMO legislation allows the EU to prosper and most importantly for patients to continue to receive transformative, potentially life-saving therapies."

Freeing the conduct of clinical trials with investigational gene therapies from the heavy EU GMO administrative burden is critical for cutting-edge biotechnology companies, added Violeta Georgieva, EuropaBios Legal Affairs Manager. The use of CRISPR/Cas9, the latest promising tool in genome editing, can be overshadowed in the EU if developers and regulators are to follow the 2018 ruling of the EU Court of Justice, which puts the controversial GMO label on the Nobel Prize-winning CRISPR technology. Our hopes are set on the European Commission to improve patient access to revolutionary treatments by exempting them from the disproportionate and outdated GMO framework.

ARM, EFPIA, and EuropaBio look forward to engaging with the European Commission and other stakeholders to find the best possible solutions to ensure that Europe is a competitive destination for the development of advanced therapies and that European patients have access to the most innovative, life-changing treatments.

Press enquiries

For more information or for media requests, please contact Stephen Majors from the Alliance for Regenerative Medicine at smajors@alliancerm.org, Andy Powrie-Smith from EFPIA at communications@efpia.eu, or Dovile Sandaraite from EuropaBio at d.sandaraite@europabio.org.

About the Alliance for Regenerative Medicine (ARM)

The Alliance for Regenerative Medicine (ARM) is the leading international advocacy organisation dedicated to realizing the promise of advanced therapy medicinal products (ATMPs).ARMpromotes legislative, regulatory, reimbursement and manufacturing initiativesin Europe and internationally to advance this innovative and transformative sector, which includes cell therapies, gene therapies and tissue-based therapies.Early products to market have demonstrated profound, durable and potentially curative benefits that are already helping thousands of patients worldwide, many of whom have no other viable treatment options. Hundreds of additional product candidates contribute to a robust pipeline of potentially life-changing ATMPs.In its 11-year history,ARMhas become the global voice of the sector, representing the interests of 380+ members worldwide and 85+ members across 15 Europeancountries, including small and large companies, academic research institutions, major medical centres and patient groups.To learn more aboutARMor to become a member, visithttp://www.alliancerm.org.

About the European Federation of Pharmaceutical Industries and Associations (EFPIA)

The European Federation of Pharmaceutical Industries and Associations (EFPIA) represents the biopharmaceutical industry operating in Europe. Through its direct membership of 36 national associations, 39 leading pharmaceutical companies and a growing number of small and medium- sized enterprises (SMEs), EFPIAs mission is to create a collaborative environment that enables our members to innovate, discover, develop and deliver new therapies and vaccines for people across Europe, as well as contribute to the European economy

About the European Association for Bioindustries (EuropaBio)

The European Association for Bioindustries (EuropaBio) promotes an innovative and dynamic European biotechnology industry. EuropaBio and its members are committed to the socially responsible use of biotechnology to improve quality of life, to prevent, diagnose, treat and cure diseases, to improve the quality and quantity of food and feedstuffs and to move towards a biobased and zero-waste economy. EuropaBio represents corporate and associate members across sectors, plus national and regional biotechnology associations which, in turn, represent over 1800 biotech SMEs. Read more about our work at http://www.europabio.org.

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ARM, EFPIA and EuropaBio Call for Advanced Therapies to be - GlobeNewswire

The public debate about genetically modified organisms (GMOs) seems to have quieted down a bit, but I suspect that is an artifact of the pandemic (all news is COVID news these days). Still, public concern about the health effects and overall safety of GMOs remains high, and is the single issue in which there is the greatest disconnect between public opinion and scientific consensus.

In a 2020 Pew Research survey 38% of Americans felt GMOs were unsafe, 27% felt they were safe, and 33% did not know. These numbers varied significantly by country, with the mean being 48/13/37 respectively. Australia was the only country to reach parity, with 31% saying they are safe and 31% unsafe, and no country had a plurality of the public believing GMOs are safe.

Meanwhile, there is a strong scientific consensus that GMO crops are indeed safe for human or animal consumption. According to a 2016 study by the National Academies of Sciences, Engineering and Medicine:

while recognizing the inherent difficulty of detecting subtle or long-term effects on health or the environment, the study committee found no substantiated evidence of a difference in risks to human health between current commercially available genetically engineered (GE) crops and conventionally bred crops, nor did it find conclusive cause-and-effect evidence of environmental problems from the GE crops.

Specifically regarding human health:

The committee carefully searched all available research studies for persuasive evidence of adverse health effects directly attributable to consumption of foods derived from GE crops but found none.

Those who wish to fearmonger about GMOs (as they do about vaccines, cell phones, or other alleged hazards) can always demand more evidence, or claim risks that have eluded existing evidence. This is always possible because it is impossible to prove zero risk for anything. And of course we legitimately need to be on the look out for evidence of subtle harm missed by prior research. But at some point the evidence showing a lack of risk is robust enough that we can be relatively confident any remaining possible risk is small enough to safely ignore.

We can also follow basic scientific principles there is no scientific reason to suspect that GMOs should be unsafe for consumption. There is no plausible mechanism, and public fears are mostly based on gross misunderstandings of the basic science, such as the false notions that only GMOs have DNA or that they can alter the genes of those who consume them. Often fears are based upon an overapplication of the precautionary principle, while ignoring a more proper risk vs benefit analysis, and further ignoring comparisons to the alternatives. It is reasonable to argue that not using genetic technology to improve agriculture is a greater risk than using it. Further, techniques for developing new cultivars that are not categorized as genetic modification may pose a higher risk of introducing harmful substances into the food chain.

There is also the point that GMO is a somewhat arbitrary category, targeting certain technologies but not others, based, it appears, on nothing but a vague ick factor. For example, mutation farming, in which radiation or chemicals are used to increase the rate of mutation in the hopes that a rare mutation will prove useful, is not considered GMO. Another example is forced hybridization, in which species that would not normally cross fertilize are forced to do so. There is also greater fear for transgenic GMOs (where a gene is inserted from a distant species) vs cisgenic (where the inserted gene is from a closely related species). Again, there is no scientific basis for this distinction, only an ick factors that derives from the idea that a fish gene is being inserted into a tomato. Such distinctions are not genetically important, however (apart from some technical aspects that dont affect the final product), as evidenced by the fact that humans and bananas share about 60% of their genes. In short there is no such thing as a fish gene.

The lines between different techniques for developing crops is getting further blurred over time, making the GMO category increasingly arbitrary and scientifically dubious. But this can have a good effect from a regulatory perspective, in that it can allow certain techniques to escape from the unnecessarily harsh regulatory environment imposed on GMOs. One such emerging category is gene-edited.

Gene-edited crops are those that are created by altering existing genes already present within the genome, rather than inserting an entirely new gene. This is an increasingly important category because of innovations like CRISPR, that makes gene editing relatively quick, cheap, and easy. In fact gene editing is becoming so powerful it may, to some extent, render the GMO category obsolete.

The political fight over how to regulate gene-edited crops is now underway. There has been partial success in some countries and regulatory zones, and failures in others. The landscape is complex, however. In the US, for example, regulating crops falls under the FDA, EPA, and USDA, and these agencies can have conflicting categories and regulations. Currently:

The three agencies regulate the characteristics of the products themselves and not the process to develop it. Gene edited crops lacking foreign genes (which trigger regulation as GMOs) and that do not pose a risk to other plants, and gene-edited food showing no food safety attributes different from those of traditionally bred crops, are not subject to pre-market regulatory evaluation. It remains the responsibility of the developer to assure that products placed on the market are safe for use and consumption.

Currently the EU and New Zealand are the only legislatures that regulate gene edited crops as if they were GMOs. Just recently the UK moved to relax regulations on gene edited crops, essentially allowing their development and use in the UK (thanks to Brexit). Canada, Japan, Brazil, Argentina, Colombia, Chile, Paraguay, and Uruguay also have relaxed regulations for gene edited crops. The rest of the world has not made a determination.

This is an important public debate to have. This is especially true because anti-GMO attitudes are one of the few topics where the knowledge deficit model of science communication is actually effective. In other words people who are anti-GMO are largely open to changing their minds if they are given more scientifically accurate information, because being anti-GMO is largely based on misinformation (rather than something harder to change like tribal affiliation or ideology). The stakes here are also very high. The experience of golden rice is a good example this is a GMO that can potentially save millions of poor children from blindness or death, and its deployment is being slowed by unscientific opposition and unreasonably burdensome regulations.

The fight for gene edited crops may be politically easier to win, and increasingly more important as technology shifts in this direction anyway.

Founder and currently Executive Editor of Science-Based Medicine Steven Novella, MD is an academic clinical neurologist at the Yale University School of Medicine. He is also the host and producer of the popular weekly science podcast, The Skeptics Guide to the Universe, and the author of the NeuroLogicaBlog, a daily blog that covers news and issues in neuroscience, but also general science, scientific skepticism, philosophy of science, critical thinking, and the intersection of science with the media and society. Dr. Novella also has produced two courses with The Great Courses, and published a book on critical thinking - also called The Skeptics Guide to the Universe.

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With an upsized production goal of 2 billion COVID-19 vaccine doses this year, Pfizer and its German partner BioNTech arent resting on their laurels now that their shot, Comirnaty, has emergency nods in the U.S., Europe and beyond. As the companies continueto build out capacity, manufacturing efficiency is getting its own boost, Pfizerrevealed.

The time it takes the companyto produce a COVID-19 vaccine batch could soon be cut from 110 days to an average of just 60, Chaz Calitri, vice president of sterile injectables, told USA Today. We call this Project Light Speed, and its called that for a reason, he said. Just in the last month, weve doubled output.

One element teed up for acceleration is DNA productionthe first step inPfizers vaccine manufacturing process, Calitri explained. Making that DNA originally took 16 days, but the process will soon take just nine or 10 days, he said.

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Production efficiencies aside, the company is also looking to dial up capacity with the addition of new manufacturing lines atall three of its U.S. plants, USA Today said.Demand for a functional shot meant Pfizer didnt have the span of several years typically required to refineits manufacturing process, so the company is improving as it goes, Calitri noted.We just went straight into commercial production," he said.

Engineers took an eye to improving manufacturing the moment vials started coming off production lines, which led the company to make a lot of really slick enhancements, he added.

A Pfizer spokesperson confirmed Calitris comments to Fierce Pharma via email.

RELATED:First-to-market Pfizer expects a whopping $15B from its COVID-19 shot in 2021

Pfizer and BioNTechs manufacturing network depends on six facilities split between Europe and the U.S. Stateside, the vaccine starts its life at Pfizers Chesterfield, Missouri, plant, where the DNA is produced. It then heads to the companys facility in Andover, Massachusetts, for transcription into mRNA, before finally making its way to Kalamazoo, Michigan for fill-finishwith lipid and lipid nanoparticle production and formulation taking place somewhere prior to that final step.Calitri heads up operations at the Kalamazoo plant.

Pfizer and BioNTechs mRNA-based vaccine last year became the first COVID-19 shot authorized in Europe and the U.S. On deck to supply hundreds of millions of doses to those two regions alone, BioNTechs CEO Uur ahin recently said the companies would boost their 2021 output target to 2 billion doses from a prior goal of 1.3 billion.

At the time, ahin pinned those production hopes on six global manufacturing sites tapped in the companies alliance, including a facility in Marburg, Germany, that he said was expected to go live by the end of February.

RELATED:Could combining Pfizer's and AZ's COVID-19 vaccines fill supply gaps? U.K. researchers aim to find out

A little more than a week later, the biotech won approval to start manufacturing itsvaccine at the Marburg site, which employs 300 people and is set to produce up to 750 million doses annually, German news outlet Hessenschau reported.

The announcement ran up against news that BioNTech was carrying out a factory upgrade in Puurs, Belgium that would allow itto deliver significantly more doses in the second quarterthough that production boost came with a catch: namely, a short-term disruption of supply in Europe, Canada and a few other countries.

Meanwhile, in a sign of the unconventional alliancesCOVID-19 has fostered, Pfizer and BioNTech recently got some added manufacturing muscle from two Big Pharma rivals. Sanofi in late January said it would produce more than 100 million Comirnaty doses in Europe in 2021, with the first deliveries from its site in Frankfurt, Germany, expected by August, a company spokesperson told Fierce Pharma.

Just a few days later, Swiss drugmaker Novartis said it would pitch in, too, agreeing to carry out fill-finish work at its facility in Stein, Switzerland, where production is pegged to start in the second quarter.

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Pfizer to nearly halve COVID-19 vaccine production timeline, sterile injectables VP says - FiercePharma

The 2021 Nobel prize in physiology or medicine has been awarded to two U.S. scientists who discovered the microscopic secrets behind the human sense of touch.

David Julius, of the University of California San Francisco, received half of the prize for using "capsaicin, a pungent compound from chili peppers that induces a burning sensation, to identify a sensor in the nerve endings of the skin that responds to heat," while Ardem Patapoutian, of the Scripps Research Institute in La Jolla, California, received the other half for using "pressure-sensitive cells to discover a novel class of sensors that respond to mechanical stimuli in the skin and internal organs," the Royal Swedish Academy of Sciences announced Monday (Oct. 4).

Their discoveries "have allowed us to understand how heat, cold and mechanical force can initiate the nerve impulses that allow us to perceive and adapt to the world around us," the Nobel Committee said in a statement. "This knowledge is being used to develop treatments for a wide range of disease conditions, including chronic pain."

Related: 7 revolutionary Nobel Prizes in medicine

The award comes with a prize of 10 million Swedish kronor ($1.15 million) to be shared equally between the two winners.

Beginning in the 1990s, the scientists pieced together the molecular pathways that translate heat and pressure detected on the skin into nerve impulses perceived by the brain. Julius and his colleagues started the work by creating a library of millions of DNA segments containing genes found in sensory nerve cells. By adding the genes one by one to cells that did not normally react to capsaicin, they eventually found that a single gene was responsible for the burning sensation associated with capsaicin. The gene they had discovered gave cells the ability to build a protein called TRPV1, which was activated at temperatures hot enough to be considered painful.

Both Julius and Patapoutian independently went on to use menthol to discover another protein, TPRM8, which was activated by cold temperatures, as well as a number of other proteins that detected a range of different temperatures.

Building on this work, Patapoutian and his colleagues created a library of 72 genes that they suspected encoded blueprints to make receptors for mechanical pressure. By painstakingly deactivating these genes one by one in cells, they discovered that one of the genes produced a protein that spurred cells to produce a tiny electrical signal each time they were prodded. The receptor they had discovered was not only vital for sensing mechanical force, but was also used in various ways to maintain blood vessels, alongside having a proposed role in adjusting the bodys blood pressure.

Soon after that, they found a second protein receptor that was vital in sensing body position and motion, a sense known as proprioception. They named the two receptors Piezo1 and Piezo2, after the Greek word for pressure.

Not only did the discoveries help explain the mechanisms behind sensory experiences like temperature and pressure, but they also opened up a world of possibilities for new drugs targeting the receptors from painkillers to drugs that could alleviate blood pressure across blood vessels and organs.

"While we understood the physiology of the senses, what we didn't understand was how we sensed differences in temperature or pressure," Oscar Marin, director of the MRC Centre for Neurodevelopmental Disorders at Kings College London told The Associated Press. "Knowing how our body senses these changes is fundamental because once we know those molecules, they can be targeted. It's like finding a lock and now we know the precise keys that will be necessary to unlock it."

Joseph Erlanger and Herbert Gasser, who shared the Nobel prize in physiology or medicine in 1944, first discovered specialized nerve cells responsive to both painful and non-painful touch.

Last year's prize went to three scientists for their discovery of hepatitis C, a blood-borne virus that causes chronic liver inflammation. The deadly disease's discovery was a breakthrough that enabled doctors to identify the virus in patients' blood and develop a cure, Live Science previously reported.

Originally published on Live Science.

Link:
Nobel prize in medicine won by US scientists who unlocked the secrets of our sense of touch - Livescience.com

Introduction

Coronary artery disease (CAD) is the major cause of death throughout the world.1 As reported by GBD 2017 Causes of Death Collaborators, the estimated years of life lost (YLLs) increased for CAD (ranked first in 2017).2 During the past decade, a marked rising trend of atherosclerosis-related burden (especially for CAD) in Eastern Asia was observed.3 Although endothelial dysfunction contributes essentially to the atherosclerosis, the molecular pathways underlying disease occurrence are not fully understood.

MicroRNAs (miRNAs) play important roles in the pathophysiology of cardiovascular diseases through the posttranscriptional control of gene networks.4,5 Among them, miR-217 was reported to aggravate atherosclerosis and promote cardiovascular dysfunction through downregulating a network of endothelial NO synthase (eNOS) activators, including vascular endothelial growth factor (VEGF).6 VEGF, a signal protein stimulating the formation of blood vessels, acted as a potential biomarker to predict the occurrence of CAD, and increased VEGF level was associated with poor coronary collateralization in patients with stable CAD.7 Besides, inhibition of miR-217 could protect against myocardial ischemia-reperfusion injury through inactivating NF-kappaB and MAPK pathways by targeting DUSP14.8 These findings highlighted a potential role of miR-217 in pathogenesis of CAD. Whether genetic variants of the miR-217 gene contributed to the occurrence of CAD was still undetermined and worthy to be explored. Thus, we aimed to conduct a casecontrol study among Chinese population to evaluate the associations of genetic variants of the miR-217 gene with CAD risk, as well as plasma level of VEGF.

In the current casecontrol study, we totally recruited 498 CAD patients and 499 healthy controls (frequency-matched by age, gender, and living areas). CAD diagnosis of any major coronary artery with diameter stenosis of more than 50%, or previous angioplasty, coronary bypass surgery, or myocardial infarction (MI) history verified by electrocardiogram (ECG) changes was evaluated by two cardiologists.9 This study has been approved by the institute committee of Jinan peoples Hospital. All participants in the study received informed consent and followed the guidelines set out in the Helsinki declaration.

Fasting venous blood was collected into plasma tubes containing 0.1% ethylenediaminetetraacetic acid (EDTA) and stored at 80C prior to analysis. Total RNAs were isolated using the miRNeasy kit (Qiagen) according to the manufacturers protocol. TaqMan miRNA assay kits (Applied Biosystems) were used for miRNA amplification, and real-time polymerase chain reaction (RT-PCR) was performed to detect miR-217, while cel-miRNA-39 was added as a spike-in control. Plasma VEGF level among the healthy controls was determined by multiplex analysis using Bioplex suspension arrays (Bio-Rad, Veenendaal, The Netherlands) according to the manufacturers specifications. All samples were thawed only once and measured three times.

TagSNPs were selected among the 1kb flanking region of the miR-217 gene according to 1000 genome CHB data (phase 3, minor allele frequency 5%, pairwise r20.8) using the Haploview 4.2 software.10 Finally, four tagSNPs, including rs6724872, rs4999828, rs10206823, and rs41291177, were determined. Genomic DNA was extracted from peripheral blood samples using QIAamp DNA blood Mini Kit (Qiagen, Hilden, Germany). Genotyping was performed by TaqMan analysis (Applied Biosystems [ABI], Foster City, CA) according to the manufacturers instructions. A randomly selected group of 10% of the samples was tested twice by different individuals with 100% concordance of results.

Statistical analyses were carried out using IBM SPSS Statistics version 22.0, while two-tailed P-values <0.05 were considered significant. All the demographic data were presented as proportions. Deviation of candidate SNPs from Hardy-Weinberg equilibrium in the control group was assessed by the goodness-of-fit 2 test. Allele frequencies and demographic variables between the two groups were assessed with chi-square tests. Odds ratios (ORs), 95% confidence levels (CIs), and corresponding P values were calculated for each SNP using logistic regression analysis, adjusted for age, gender, smoking status, drinking status, diabetes, and hypertension.

Table 1 lists the comparison of clinical features between 498 CAD cases and 499 controls. The results showed that there was no significant difference in age, gender, drinking status, diabetes and hypertension (P > 0.05). However, compared with the control group, the patients have higher percentage of smokers (controls vs cases: 26.7% vs 42.4%; P < 0.001).

Table 1 Clinical Characteristics of CAD Cases and Controls

We first evaluated the association between plasma level of miR-217 and CAD risk to validate the role of miR-217 in CAD development. As shown in Figure 1, plasma level of miR-217 was analyzed in 50 randomly selected patients with CAD and controls. We found plasma level of miR-217 in CAD cases was significantly higher than that in controls (P < 0.001).

Figure 1 Plasma level of miR-217 and CAD risk. Plasma level of miR-217 was analyzed in 50 randomly selected patients with CAD and controls, and plasma level of miR-217 in CAD cases was significantly higher than that in controls (P < 0.001).

As shown in Table 2, all four tagSNPs (rs6724872, rs4999828, rs10206823, and rs41291177) were in Hardy-Weinberg equilibrium in healthy controls, which indicated that the sampled subjects were representative of the population without any deviation of genotype frequencies (P>0.05). Of the four tagSNPs in the miR-217 gene region, rs6724872 and rs4999828 were significantly associated with increased risk of CAD (P value was smaller than 0.05 even after Bonferroni multiple adjustment). Compared with the G allele, C allele of rs6724872 was significantly associated with 1.73-fold increased risk of CAD (95% CI: 1.252.39; P=0.001). While C allele of rs4999828 was significantly associated with 1.75-fold increased risk of CAD, compared with T allele (95% CI: 1.342.29; P=4105).

Table 2 Associations Between Genetic Variations and Risk of CAD

To further evaluate the influence of susceptibility SNPs upon plasma level of VEGF, we compared the VEGF level among healthy controls with different genotypes of rs6724872 and rs4999828. As shown in Figure 2, with the increase in number of minor alleles, the plasma level of VEGF increased significantly for both rs6724872 and rs4999828 (P < 0.001). This means rs6724872 and rs4999828 were significantly associated with higher level of VEGF.

Figure 2 Circulating level of VEGF in subjects with different miR-217 genotypes. Plasma VEGF level among the healthy controls were determined by multiplex analysis using Bioplex suspension arrays. With the increasement of number of minor alleles, the plasma level of VEGF increased significantly for both rs6724872 and rs4999828 (P < 0.001).

Coronary heart disease is a common and frequent disease, which brings serious trouble to peoples quality of life.2,11 The exploration of the etiology of CAD is a complex and systematic project, and researchers have explored multiple aspects and perspectives.12,13 The current study explored associations between the associations of genetic variants of the miR-217 gene with CAD risk, as well as plasma level of VEGF, using a casecontrol study design. We found plasma level of miR-217, rs6724872 and rs4999828 were significantly associated with increased risk of CAD, as well as higher level of VEGF. These findings highlighted the important role of miR-217 in the pathogenesis of CAD and potential targets for intervention.

MiRNAs are implicated in the regulation of proliferation and apoptosis of endothelial cells, induction of immune responses and different stages of plaque formation, which finally results atherosclerosis and CAD.5,14,15 A previous meta-analysis identified that a total of 48 dysregulated miRNAs were confirmed for their role in CAD development, while MiR-122-5p and miR-133a-3p may be valuable biomarkers for CAD.16 Another two studies confirmed that predictive value of miRNA-21 and miRNA-126 on coronary restenosis after percutaneous coronary intervention (PCI) in patients with CAD.17,18 Previously, miR-217 was most studied in the field of cancer biology.1923 Zhao et al reported that downregulated miR-217 could regulate KRAS and function as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC).19 Further, Menghini et al pinpointed miR-217 as an endogenous inhibitor of SirT1 was potentially amenable to the prevention of endothelial dysfunction.24 Recently, Yebenes then reported that miR-217 could aggravate atherosclerosis and promote cardiovascular dysfunction.6 Taking the findings above together, it is important to extensively explore the role of miR-217 in the pathogenesis of CAD and to investigate the association of its genetic variants with the risk of disease development.

Genetic variants in miRNAs have been widely explored for their functions among pathophysiological mechanism of cardiovascular diseases, and offer new insight into the causal role of microRNAs in CAD.2531 Glinsky et al revealed identifies a consensus disease phenocode through a SNP-guided microRNA map of fifteen common human disorders.31 Ghanbari et al systematically evaluated 230 variants located within miRNA-binding sites in the 3-untranslated region of 155 cardiometabolic genes, and 37 were functional in their corresponding genomic loci.28 In the current study, rs6724872 and rs4999828 were significantly associated with increased risk of CAD, as well as higher level of VEGF, which means the important role in CAD development. Using RegulomeDB 2.0, we found both rs6724872 and rs4999828 were located in the TF binding and DNase peak region.32 The findings of HaploReg v4.1 also validated their functions in gene regulation.33

Conclusively, We found rs6724872 and rs4999828 were significantly associated with increased risk of CAD, as well as higher level of VEGF. Although these findings need further validation in larger cohorts for definitive results, they reveal new mechanisms by which genetic variations in miR-217 gene may coordinate the development of CAD. The gathered evidence could be further exploited in prevention strategies or screening protocols for CAD.

This study was supported by medical and health science and technology development planning project of Shandong Province (No. 202003011008) and the second batch of science and technology projects of Jinan Health Committee (2020-03-55).

The authors declare that they have no conflict of interest.

1. Hata J, Kiyohara Y. Epidemiology of stroke and coronary artery disease in Asia. Circ J. 2013;77(8):19231932. doi:10.1253/circj.CJ-13-0786

2. Collaborators GBDCoD. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 19802017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):17361788.

3. Wong MC, Zhang DX, Wang HH. Rapid emergence of atherosclerosis in Asia: a systematic review of coronary atherosclerotic heart disease epidemiology and implications for prevention and control strategies. Curr Opin Lipidol. 2015;26(4):257269. doi:10.1097/MOL.0000000000000191

4. Widmer RJ, Lerman LO, Lerman A. MicroRNAs: small molecule, big potential for coronary artery disease. Eur Heart J. 2016;37(22):17501752. doi:10.1093/eurheartj/ehw067

5. Ghafouri-Fard S, Gholipour M, Taheri M. Role of MicroRNAs in the pathogenesis of coronary artery disease. Front Cardiovasc Med. 2021;8:632392. doi:10.3389/fcvm.2021.632392

6. de Yebenes VG, Briones AM, Martos-Folgado I, et al. Aging-associated miR-217 aggravates atherosclerosis and promotes cardiovascular dysfunction. Arterioscler Thromb Vasc Biol. 2020;40(10):24082424. doi:10.1161/ATVBAHA.120.314333

7. Sun Z, Shen Y, Lu L, et al. Increased serum level of soluble vascular endothelial growth factor receptor-1 is associated with poor coronary collateralization in patients with stable coronary artery disease. Circ J. 2014;78(5):11911196. doi:10.1253/circj.CJ-13-1143

8. Li Y, Fei L, Wang J, Niu Q. Inhibition of miR-217 protects against myocardial ischemia-reperfusion injury through inactivating NF-kappaB and MAPK pathways. Cardiovasc Eng Technol. 2020;11(2):219227. doi:10.1007/s13239-019-00452-z

9. Li J, Zhang Y, Guo X, Wu Y, Huang R, Han X. Circulating level of monocyte chemoattractant protein-1 and risk of coronary artery disease: a case-control and Mendelian randomization study. Pharmgenomics Pers Med. 2021;14:553559.

10. Barrett JC. Haploview: visualization and analysis of SNP genotype data. Cold Spring Harb Protoc. 2009;2009(10):pdbip71. doi:10.1101/pdb.ip71

11. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146e603.

12. Manfrini O, Yoon J, van der Schaar M, et al. Sex differences in modifiable risk factors and severity of coronary artery disease. J Am Heart Assoc. 2020;9(19):e017235. doi:10.1161/JAHA.120.017235

13. Lonnebakken MT. Cardiometabolic risk factors and coronary artery disease in women. J Womens Health (Larchmt). 2020;29(12):14891490. doi:10.1089/jwh.2020.8755

14. Sanlialp M, Dodurga Y, Uludag B, et al. Peripheral blood mononuclear cell microRNAs in coronary artery disease. J Cell Biochem. 2020;121(4):30053009. doi:10.1002/jcb.29557

15. Zhang X, Cai H, Zhu M, Qian Y, Lin S, Li X. Circulating microRNAs as biomarkers for severe coronary artery disease. Medicine (Baltimore). 2020;99(17):e19971. doi:10.1097/MD.0000000000019971

16. Wang -S-S, Wu L-J, Li -J-J-H, Xiao H-B, He Y, Yan Y-X. A meta-analysis of dysregulated miRNAs in coronary heart disease. Life Sci. 2018;215:170181. doi:10.1016/j.lfs.2018.11.016

17. Dai H, Wang J, Shi Z, Ji X, Huang Y, Zhou R. Predictive value of miRNA-21 on coronary restenosis after percutaneous coronary intervention in patients with coronary heart disease: a protocol for systematic review and meta-analysis. Medicine (Baltimore). 2021;100(10):e24966. doi:10.1097/MD.0000000000024966

18. Qiu X, Wang J, Shi Z, Ji X, Huang Y, Dai H. Predictive value of miRNA-126 on in-stent restenosis in patients with coronary heart disease: a protocol for meta-analysis and bioinformatics analysis. Medicine (Baltimore). 2021;100(22):e25887. doi:10.1097/MD.0000000000025887

19. Zhao WG, Yu SN, Lu ZH, Ma YH, Gu YM, Chen J. The miR-217 microRNA functions as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS. Carcinogenesis. 2010;31(10):17261733. doi:10.1093/carcin/bgq160

20. Deng S, Zhu S, Wang B, et al. Chronic pancreatitis and pancreatic cancer demonstrate active epithelial-mesenchymal transition profile, regulated by miR-217-SIRT1 pathway. Cancer Lett. 2014;355(2):184191. doi:10.1016/j.canlet.2014.08.007

21. Nishioka C, Ikezoe T, Yang J, Nobumoto A, Tsuda M, Yokoyama A. Downregulation of miR-217 correlates with resistance of Ph(+) leukemia cells to ABL tyrosine kinase inhibitors. Cancer Sci. 2014;105(3):297307. doi:10.1111/cas.12339

22. Popov A, Szabo A, Mandys V. Small nucleolar RNA U91 is a new internal control for accurate microRNAs quantification in pancreatic cancer. BMC Cancer. 2015;15:774. doi:10.1186/s12885-015-1785-9

23. Xi S, Inchauste S, Guo H, et al. Cigarette smoke mediates epigenetic repression of miR-217 during esophageal adenocarcinogenesis. Oncogene. 2015;34(44):55485559. doi:10.1038/onc.2015.10

24. Menghini R, Casagrande V, Cardellini M, et al. MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation. 2009;120(15):15241532. doi:10.1161/CIRCULATIONAHA.109.864629

25. Borghini A, Andreassi MG. Genetic polymorphisms offer insight into the causal role of microRNA in coronary artery disease. Atherosclerosis. 2018;269:6370. doi:10.1016/j.atherosclerosis.2017.12.022

26. Joehanes R, Zhang X, Huan T, et al. Integrated genome-wide analysis of expression quantitative trait loci aids interpretation of genomic association studies. Genome Biol. 2017;18(1):16. doi:10.1186/s13059-016-1142-6

27. Kaudewitz D, Skroblin P, Bender LH, et al. Association of MicroRNAs and YRNAs with platelet function. Circ Res. 2016;118(3):420432. doi:10.1161/CIRCRESAHA.114.305663

28. Ghanbari M, Franco OH, de Looper HW, Hofman A, Erkeland SJ, Dehghan A. Genetic variations in MicroRNA-binding sites affect MicroRNA-mediated regulation of several genes associated with cardio-metabolic phenotypes. Circ Cardiovasc Genet. 2015;8(3):473486. doi:10.1161/CIRCGENETICS.114.000968

29. Li L, He M, Zhou L, et al. A solute carrier family 22 member 3 variant rs3088442 G>A associated with coronary heart disease inhibits lipopolysaccharide-induced inflammatory response. J Biol Chem. 2015;290(9):53285340. doi:10.1074/jbc.M114.584953

30. Miller CL, Haas U, Diaz R, et al. Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation. PLoS Genet. 2014;10(3):e1004263. doi:10.1371/journal.pgen.1004263

31. Glinsky GV. An SNP-guided microRNA map of fifteen common human disorders identifies a consensus disease phenocode aiming at principal components of the nuclear import pathway. Cell Cycle. 2008;7(16):25702583. doi:10.4161/cc.7.16.6524

32. Boyle AP, Hong EL, Hariharan M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22(9):17901797. doi:10.1101/gr.137323.112

33. Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40(Databaseissue):D930934. doi:10.1093/nar/gkr917

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Association of Genetic Variants in miR-217 Gene with Risk of Coronary | PGPM - Dove Medical Press

Published: Oct. 4, 2021 at 6:00 AM EDT

NEW YORK, Oct. 4, 2021 /PRNewswire/ -- BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of cellular therapies for neurodegenerative diseases, announced today that Stacy Lindborg, Ph.D., Executive Vice President and Head of Global Clinical Research, will deliver a presentation at the2021 Cell & Gene Meeting on the Mesa, being held as a hybrid conferenceOctober 12-14, and October 19-20, 2021.

Dr. Lindborg's presentation highlights the expansion of Brainstorm's technology portfolio to include autologous and allogeneic product candidates, covering multiple neurological diseases. The most progressed clinical development program, which includes a completed phase 3 trial of NurOwn in ALS patients, remains the highest priority for Brainstorm. Brainstorm is committed to pursuing the best and most expeditious path forward to enable patients to access NurOwn.

Dr. Lindborg's presentation will be in the form of an on-demand webinar that will be available beginning October 12. Those who wish to listen to the presentation are required to registerhere. At the conclusion of the 2021 Cell & Gene Meeting on the Mesa, a copy of the presentation will also be available in the "Investors and Media" section of the BrainStorm website underEvents and Presentations.

About the 2021 Cell & Gene Meeting on the Mesa

The meeting will feature sessions and workshops covering a mix of commercialization topics related to the cell and gene therapy sector including the latest updates on market access and reimbursement schemes, international regulation harmonization, manufacturing and CMC challenges, investment opportunities for the sector, among others. There will be over 135 presentations by leading public and private companies, highlighting technical and clinical achievements over the past 12 months in the areas of cell therapy, gene therapy, gene editing, tissue engineering and broader regenerative medicine technologies.

The conference will be delivered in a hybrid format to allow for an in-person experience as well as a virtual participation option. The in-person conference will take place October 12-14 in Carlsbad, CA. Virtual registrants will have access to all content via livestream during program dates. Additionally, all content will be available on-demand within 24 hours of the live program time. Virtual partnering meetings will take place October 19-20 via Zoom.

About NurOwn

The NurOwntechnology platform (autologous MSC-NTF cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells are designed to effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwntechnology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug designation status from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has completed a Phase 3 pivotal trial in ALS (NCT03280056); this trial investigated the safety and efficacy of repeat-administration of autologous MSC-NTF cells and was supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). BrainStorm completed under an investigational new drug application a Phase 2 open-label multicenter trial (NCT03799718) of autologous MSC-NTF cells in progressive multiple sclerosis (MS) and was supported by a grant from the National MS Society (NMSS).

For more information, visit the company's website atwww.brainstorm-cell.com.

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future NurOwnmanufacturing and clinical development plans, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may," "should," "would," "could," "will," "expect,""likely," "believe," "plan," "estimate," "predict," "potential," and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, the prospects for regulatory approval of BrainStorm's NurOwntreatment candidate, the initiation, completion, and success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwntreatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture, or to use third parties to manufacture, and commercialize the NurOwntreatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

ContactsInvestor Relations:Eric GoldsteinLifeSci Advisors, LLCPhone: +1 646.791.9729egoldstein@lifesciadvisors.com

Media:Paul TyahlaSmithSolvePhone: + 1.973.713.3768Paul.tyahla@smithsolve.com

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BrainStorm to Present at the 2021 Cell & Gene Meeting on the Mesa - WWNY

When oncologists talk about cancer targets, theyre usually referring to mutated genes that can be thwarted with drugs. Researchers at the University of Pennsylvania used gene-editing technology CRISPR to elucidate a different sort of target in acute myeloid leukemia (AML)and to uncover a way to target it with drugs.

A team at Penns medical school discovered that an epigenetic regulatory protein called ZMYND8 governs the expression of genes that are critical for the growth and survival of AML cells. Inhibiting ZMYND8 in mouse models shrank tumors. The researchers also found a biomarker that they believe could predict which patients are likely to respond to ZMYND8 inhibition, they reported in the journal Molecular Cell.

AML is one of the hardest leukemias to treat, with a five-year survival rate of about 27% in adults. The Penn team had been searching for precision medicine approaches that could improve the prognosis for adults with AML, and they turned to CRISPR for help.

ZMYND8 is known as a histone reader in cancer that can recognize epigenetic changes and influence gene expression involved in metastasis.

Using CRISPR, the Penn team disrupted various functions of proteins in cancer cells and mapped their functions on a molecular level. When they blocked the epigenetic reader function of ZMYND8 in mouse models, it not only caused tumors to shrink, but also improved survival, they said in a statement. With CRISPR, they were able to pinpoint a pocket on ZMYND8 that they believe could be targeted with drugs.

RELATED: Novartis-backed Penn study proposes boosting CAR-T responses in CLL by waking up 'war weary' T cells

Several efforts to develop new treatments for AML have hit roadblocks of late. The FDA placed a hold on trials of Aprea Therapeutics eprenetapopt in AML after worrisome side effects appeared in a trial of the drug in myelodysplastic syndrome. Amgen had been developing a bispecific antibody for AML, AMG 427, but stopped a phase 1 trial after some patients developed the dangerous side effect cytokine release syndrome. The company is now investigating ways to optimize the treatment approach, a spokesperson said earlier this month.

Several immuno-oncology approaches to AML are under development, including engineered natural killer cell therapies, and researchers are investigating a range of targeted approaches such as combining MDM2 and BET blockers.

The Penn researchers wanted to see whether they could predict how sensitive AML cells might be to ZMYND8 inhibition, so they turned to blood samples from patients treated at Penn Medicine. They found that high expression of a particular gene in those cells, IRF8, could serve as a biomarker of response to ZMYND8 inhibition.

CRISPR revealed here, for the time, an unexpected epigenetic-linked molecular circuity that AML is dependent on, and one that we can potentially manipulate, said co-author Shelley Berger, Ph.D., professor at the Perelman School of Medicine and director of the Penn Epigenetics Institute, in the statement. It opens a new door toward better treatments for these patients using next-generation epigenetic inhibitors.

Read more:
CRISPR pinpoints new leukemia target and a 'pocket' that could make it druggable - FierceBiotech

We live in a unique time when for the first time in human history there is a real opportunity to extend our lives dramatically. Recent scientific discoveries and technological breakthroughs that soon will translate into affordable and accessible life-extending tools will let us break the sound barrier of the current known record of 122 years. I am talking about breakthroughs in genetic engineering, regenerative medicine, healthcare hardware, and health data.

Very soon, slowing, reversing, or even ending aging will become a universally accepted ambition within the healthcare community. Technology is converging to make this a certainty. Developments in the understanding and manipulation of our genes and cells, in the development of small-scale health diagnostics, and in the leveraging of data for everything from drug discovery to precision treatment of disease are radically changing how we think about healthcare and aging.

When I speak of the Longevity Revolution, what I really mean is the cumulative effect of multiple breakthroughs currently underway across several fields of science and technology. Together, these parallel developments are forming the beginning of a hockey-stick growth curve that will deliver world-changing outcomes.

Completed in 2003, the Human Genome Project successfully sequenced the entire human genomeall 3 billion nucleotide base pairs representing some 25,000 individual genes. The project, arguably one of the most ambitious scientific undertakings in history, cost billions of dollars and took 13 years to complete. Today, your own genome can be sequenced in as little time as a single afternoon, at a laboratory cost of as little as $200.

The consequences of this feat are nothing short of revolutionary. Gene sequencing allows us to predict many hereditary diseases and the probability of getting cancer. This early benefit of gene sequencing became widely known when Angelina Jolie famously had a preventative double mastectomy after her personal genome sequencing indicated a high vulnerability to breast cancer. Genome sequencing helps scientists and doctors understand and develop treatments for scores of common and rare diseases. Along with advances in artificial intelligence, it helps determine medical treatments precisely tailored to the individual patient.

Longevity scientists have even identified a number of so-called longevity genes that can promise long and healthy lives to those who possess them. Scientists now understand far better than ever before the relationship between genes and aging. And while our genes do not significantly change from birth to death, our epigenomethe system of chemical modifications around our genes that determine how our genes are expresseddoes. The date on your birth certificate, it turns out, is but a single way to determine age. The biological age of your epigenome, many longevity scientists now believe, is far more important.

Best of all, however, science is beginning to offer ways to alter both your genome and epigenome for a healthier, longer life. New technologies like CRISPR-Cas9 and other gene-editing tools are empowering doctors with the extraordinary ability to actually insert, delete, or alter an individuals genes. In the not terribly distant future, we will be able to remove or suppress genes responsible for diseases and insert or amplify genes responsible for long life and health.

Gene editing is just one of the emerging technologies of the genetic revolution: Gene therapy works by effectively providing cells with genes that produce necessary proteins in patients whose own genes cannot produce them. This process is already being applied to a few rare diseases, but it will soon become a common and incredibly effective medical approach. The FDA expects to approve 10 to 20 such therapies by the year 2025.

Another major transformation driving the Longevity Revolution is the field of regenerative medicine. During aging, the bodys systems and tissues break down, as does the bodys ability to repair and replenish itself. For that reason, even those who live very long and healthy lives ultimately succumb to heart failure, immune system decline, muscle atrophy, and other degenerative conditions. In order to achieve our ambition of living to 200, we need a way to restore the body in the same way we repair a car or refurbish a home.

Several promising technologies are now pointing the way to doing just that. While it is still quite early, there are already a few FDA-approved stem cell therapies in the United States targeting very specific conditions. Stem cellscells whose job it is to generate all the cells, tissues, and organs of your bodygradually lose their ability to create new cells as we age. But new therapies, using patients own stem cells, are working to extend the bodys ability to regenerate itself. These therapies hold promise for preserving our vision, cardiac function, joint flexibility, and kidney and liver health; they can also be used to repair spinal injuries and help treat a range of conditions from diabetes to Alzheimers disease. The FDA has approved 10 stem cell treatments, with more likely on the way.

Its one thing to replenish or restore existing tissues and organs using stem cells, but how about growing entirely new organs? As futuristic as that sounds, it is already beginning to happen. Millions of people around the world who are waiting for a new heart, kidney, lung, pancreas, or liver will soon have their own replacement organs made to order through 3D bio-printing, internal bioreactors, or new methods of xenotransplantation, such as using collagen scaffoldings from pig lungs and hearts that are populated with the recipients own human cells.

Even if this generation of new biological organs fails, mechanical solutions will not. Modern bioengineering has successfully restored lost vision and hearing in humans using computer sensors and electrode arrays that send visual and auditory information directly to the brain. A prosthetic arm developed at Johns Hopkins is one of a number of mechanical limbs that not only closely replicate the strength and dexterity of a real arm but also can be controlled directly by the wearers mindjust by thinking about the desired movement. Today, mechanical exoskeletons allow paraplegics to run marathons, while artificial kidneys and mechanical hearts let those with organ failure live on for years beyond what was ever previously thought possible!

The third development underpinning the Longevity Revolution will look more familiar to most: connected devices. You are perhaps already familiar with common wearable health-monitoring devices like the Fitbit, Apple Watch, and ura Ring. These devices empower users to quickly obtain data on ones own health. At the moment, most of these insights are relatively trivial. But the world of small-scale health diagnostics is advancing rapidly. Very soon, wearable, portable, and embeddable devices will radically reduce premature death from diseases like cancer and cardiovascular disease, and in doing so, add years, if not decades, to global life expectancy.

[Photo: BenBella Books]The key to this part of the revolution is early diagnosis. Of the nearly 60 million lives lost around the globe each year, more than 30 million are attributed to conditions that are reversible if caught early. Most of those are noncommunicable diseases like coronary heart disease, stroke, and chronic obstructive pulmonary disease (bronchitis and emphysema). At the moment, once you have gone for your yearly physical exams, stopped smoking, started eating healthy, and refrained from having unprotected sex, avoiding life-threatening disease is a matter that is largely out of your hands. We live in a world of reactive medicine. Most people do not have advanced batteries of diagnostic tests unless theyre experiencing problems. And for a large percentage of the worlds population, who live in poor, rural, and remote areas with little to no access to diagnostic resources, early diagnosis of medical conditions simply isnt an option.

But not for long. Soon, healthcare will move from being reactive to being proactive. The key to this shift will be low-cost, ubiquitous, connected devices that constantly monitor your health. While some of these devices will remain external or wearable, others will be embedded under your skin, swallowed with your breakfast, or remain swimming through your bloodstream at all times. They will constantly monitor your heart rate, your respiration, your temperature, your skin secretions, the contents of your urine and feces, free-floating DNA in your blood that may indicate cancer or other disease, and even the organic contents of your breath. These devices will be connected to each other, to apps that you and your healthcare provider can monitor, and to massive global databases of health knowledge. Before any type of disease has a chance to take a foothold within your body, this armory of diagnostic devices will identify exactly what is going on and provide a precise, custom-made remedy that is ideal just for you.

As a result, the chance of your disease being diagnosed early will become radically unshackled from the limitations of cost, convenience, and medical knowledge. The condition of your body will be maintained as immaculately as a five-star hotel, and almost nobody will die prematurely of preventable disease.

There is one final seismic shift underpinning the Longevity Revolution, and its a real game-changer. Pouring forth from all of these digital diagnostic devices, together with conventional medical records and digitized research results, is a torrent of data so large it is hard for the human mind to even fathom it. This data will soon become grist for the mill of powerful artificial intelligence that will radically reshape every aspect of healthcare as we know it.

Take drug discovery, for instance. In the present day, it takes about 12 years and $2 billion to develop a new pharmaceutical. Researchers must painstakingly test various organic and chemical substances, in myriad combinations, to try to determine the material candidates that have the best chance of executing the desired medical effect. The drugs must be considered for the widest range of possible disease presentations, genetic makeup, and diets of targeted patients, side effects, and drug interactions. There are so many variables that it is little short of miraculous that our scientists have done so much in the field of pharmaceutical development on their own. But developing drugs and obtaining regulatory approval is a long and cash-intensive process. The result is expensive drugs that largely ignore rarer conditions.

AI and data change that reality. Computer models now look at massive databases of patient genes, symptoms, disease species, and millions of eligible compounds to quickly determine which material candidates have the greatest chance of success, for which conditions, and according to what dose and administration. In addition to major investments by Big Pharma, there are currently hundreds of startups working to implement the use of AI to radically reshape drug discovery, just as we saw happen in the race to develop COVID-19 vaccines. The impact that this use of AI and data will have on treating or even eliminating life-threatening diseases cannot be overstated.

But that is not the only way that artificial intelligence is set to disrupt healthcare and help set the Longevity Revolution in motion. It will also form the foundation of precision medicinethe practice of custom-tailoring health treatments to the specific, personal characteristics of the individual.

Today, healthcare largely follows a one-size-fits-all practice. But each of us has a very unique set of personal characteristics, including our genes, microbiome, blood type, age, gender, size, and so on. AI will soon be able to access and analyze enormous aggregations of patient data pulled together from medical records, personal diagnostic devices, research studies, and other sources to deliver highly accurate predictions, diagnoses, and treatments, custom-tailored to the individual. As a result, healthcare will increasingly penetrate remote areas, becoming accessible to billions of people who today lack adequate access to medical care.

I predict that the development of AI in healthcare will change how we live longer, healthier lives as radically as the introduction of personal computers and the internet changed how we work, shop, and interact. Artificial intelligence will eliminate misdiagnosis; detect cancer, blood disease, diabetes, and other killers as early as possible; radically accelerate researchers understanding of aging and disease; and reestablish doctors as holistic care providers who actually have time for their patients. In as little as 10 years time, we will look back at the treatment of aging and disease today as quite naive.

The Longevity Revolution lives not in the realm of science fiction but in the reality of academic research laboratories and commercial technology R&D centers. The idea of aging as a fixed and immutable quality of life that we have no influence upon is ready to be tossed into the dustbin of history.

Sergey Young is a renowned VC, longevity visionary, and founder of the $100 million Longevity Vision Fund. This is an adapted excerpt from The Science and Technology of Growing Young, with permission by BenBella Books.

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These 4 tech breakthroughs could help end aging - Fast Company

BOSTON, August 26, 2021--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced publication in The New England Journal of Medicine (NEJM) of results from a Phase 3 study of TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in people with cystic fibrosis (CF) ages 12 years and older who have one copy of the F508del mutation and one gating (F/G) or residual function (F/RF) mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The manuscript includes data on primary and key secondary endpoints, which were previously reported and showed statistically significant and clinically meaningful improvements in lung function and sweat chloride, when compared to active control (either ivacaftor or tezacaftor/ivacaftor), as well as more detailed efficacy and safety data, including subgroup efficacy analyses.

"This study is the third of three Phase 3 clinical trials in the TRIKAFTA program in the 12 years and older age group. Consistent with the prior outcomes, these results show clinically meaningful improvements in pulmonary function, sweat chloride and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores," said Carmen Bozic, M.D., Executive Vice President and Chief Medical Officer, Vertex. "These results are especially notable given that all patients were treated with a CFTR modulator prior to initiating TRIKAFTA."

"The outcomes within this study, in particular those from the subgroup efficacy analysis by F/G and F/RF, are remarkable because they demonstrate additional benefit on top of standard of care and build further confidence for clinicians to treat people with CF who may have these mutations," said Steven Rowe, M.D., Director, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham.

Study 445-104

The data published today are from a global Phase 3, randomized, double-blind, parallel-group study. All patients had a 4-week run-in period of either ivacaftor or tezacaftor/ivacaftor. Following the run-in, 258 patients were randomized to receive TRIKAFTA or to remain on their prior regimen of ivacaftor or tezacaftor/ivacaftor for 8 weeks. Baseline was measured at the end of the run-in period, prior to the start of the 8-week treatment period. TRIKAFTA improved the percent predicted forced expiratory volume in 1 second (ppFEV1) by 3.7 percentage points (95% CI, 2.8 to 4.6; P<0.001) from baseline and by 3.5 percentage points (95% CI, 2.2 to 4.7; P<0.001) vs. active control and improved sweat chloride concentration by 22.3 mmol/liter (95% CI, 24.5 to 20.2; P<0.001) from baseline and by 23.1 mmol/liter (95% CI, 26.1 to 20.1; P<0.001) vs. active control. The change in the CFQ-R respiratory domain score was +10.3 points from baseline (95% CI, 8.0 to 12.7) and +8.7 points vs. active control (95% CI, 5.3 to 12.1). Subgroup analyses of patients with F/G and F/RF genotypes are also included in the manuscript. Safety data were consistent with those observed in previous Phase 3 studies with TRIKAFTA.

Story continues

About Cystic Fibrosis

Cystic Fibrosis (CF) is a rare, life-shortening genetic disease affecting more than 80,000 people globally. CF is a progressive, multi-system disease that affects the lungs, liver, GI tract, sinuses, sweat glands, pancreas and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. Children must inherit two defective CFTR genes one from each parent to have CF. While there are many different types of CFTR mutations that can cause the disease, the vast majority of all people with CF have at least one F508del mutation. These mutations, which can be determined by a genetic test, or genotyping test, lead to CF by creating non-working and/or too few CFTR proteins at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the early 30s.

INDICATION AND IMPORTANT SAFETY INFORMATION FOR TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor) TABLETS

What is TRIKAFTA?

TRIKAFTA is a prescription medicine used for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who have at least one copy of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or another mutation that is responsive to treatment with TRIKAFTA. Patients should talk to their doctor to learn if they have an indicated CF gene mutation. It is not known if TRIKAFTA is safe and effective in children under 6 years of age.

Patients should not take TRIKAFTA if they take certain medicines or herbal supplements, such as: antibiotics such as rifampin or rifabutin; seizure medicines such as phenobarbital, carbamazepine, or phenytoin; St. Johns wort.

Before taking TRIKAFTA, patients should tell their doctor about all of their medical conditions, including if they: have kidney problems; have or have had liver problems; are pregnant or plan to become pregnant because it is not known if TRIKAFTA will harm an unborn baby; or are breastfeeding or planning to breastfeed because it is not known if TRIKAFTA passes into breast milk.

TRIKAFTA may affect the way other medicines work, and other medicines may affect how TRIKAFTA works. Therefore, the dose of TRIKAFTA may need to be adjusted when taken with certain medicines. Patients should especially tell their doctor if they take antifungal medicines such as ketoconazole, itraconazole, posaconazole, voriconazole, or fluconazole; antibiotics including telithromycin, clarithromycin, or erythromycin.

TRIKAFTA may cause dizziness in some people who take it. Patients should not drive a car, operate machinery, or do anything that requires alertness until they know how TRIKAFTA affects them.

Patients should avoid food or drink that contains grapefruit while they are taking TRIKAFTA.

TRIKAFTA can cause serious side effects, including:

High liver enzymes in the blood, which is a common side effect in people treated with TRIKAFTA. These can be serious and may be a sign of liver injury. The patient's doctor will do blood tests to check their liver before they start TRIKAFTA, every 3 months during the first year of taking TRIKAFTA, and every year while taking TRIKAFTA. Patients should call their doctor right away if they have any of the following symptoms of liver problems: pain or discomfort in the upper right stomach (abdominal) area; yellowing of the skin or the white part of the eyes; loss of appetite; nausea or vomiting; dark, amber-colored urine.

Abnormality of the eye lens (cataract) has happened in some children and adolescents treated with TRIKAFTA. If the patient is a child or adolescent, their doctor should perform eye examinations before and during treatment with TRIKAFTA to look for cataracts.

The most common side effects of TRIKAFTA include headache, upper respiratory tract infection (common cold) including stuffy and runny nose, stomach (abdominal) pain, diarrhea, rash, increase in liver enzymes, increase in a certain blood enzyme called creatine phosphokinase, flu (influenza), inflamed sinuses, and increase in blood bilirubin.

These are not all the possible side effects of TRIKAFTA. Please click the product link to see the full Prescribing Information for TRIKAFTA.

About Vertex

Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has multiple approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational small molecule medicines in other serious diseases where it has deep insight into causal human biology, including pain, alpha-1 antitrypsin deficiency and APOL1-mediated kidney diseases. In addition, Vertex has a rapidly expanding pipeline of cell and genetic therapies for diseases such as sickle cell disease, beta thalassemia, Duchenne muscular dystrophy and type 1 diabetes mellitus.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 11 consecutive years on Science magazine's Top Employers list and a best place to work for LGBTQ equality by the Human Rights Campaign. For company updates and to learn more about Vertex's history of innovation, visit http://www.vrtx.com or follow us on Facebook, Twitter, LinkedIn, YouTube and Instagram.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Dr. Carmen Bozic and Dr. Steven Rowe in this press release and statements regarding the potential benefits of TRIKAFTA and our anticipated efforts to expand the indication for TRIKAFTA globally. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from a limited number of patients may not be indicative of final clinical trial results, that data from the company's development programs, including its programs with its collaborators, may not support registration or further development of its compounds due to safety, efficacy, or other reasons, and other risks listed under the heading "Risk Factors" in Vertex's most recent annual report filed with the Securities and Exchange Commission at http://www.sec.gov and available through the company's website at http://www.vrtx.com. You should not place undue reliance on these statements or the scientific data presented. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

View source version on businesswire.com: https://www.businesswire.com/news/home/20210826005091/en/

Contacts

Vertex Pharmaceuticals Incorporated Investors: Michael Partridge, +1 617-341-6108orBrenda Eustace, +1 617-341-6187orManisha Pai, +1 617-429-6891

Media: mediainfo@vrtx.com orU.S.: +1 617-341-6992orHeather Nichols: +1 617-839-3607orInternational: +44 20 3204 5275

Originally posted here:
Vertex Announces Publication in The New England Journal of Medicine of Phase 3 Results for TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor)...