Daily Archives: May 9, 2021

Cell and gene therapies rapid penetration in clinical trials globally is testimony to the incredible potential these in understanding, treating, and curing diseases. The cell and gene therapy clinical trials market is rapidly evolving, touching numerous frontiers in personalized medicine, especially for chronic diseases. A number of gene therapies approved by the U.S. FDA reinforces the potential. Pharmaceutical companies in clinical trials that test cell and gene therapies have bloomed strikingly, most notably in oncology, eye diseases, and rare hereditary diseases. A partial list of the top diseases that attract massive attention of contract research organizations in cell and gene therapy market are type 1 diabetes, Parkinsons disease, spinal cord injuries, amyotrophic lateral sclerosis, the Alzheimers disease, and osteoarthritis.

The number of cell and gene therapies is seeing marked increase year over year. According to an estimate, there were more than a thousand cell and gene therapy clinical trials by 2019. To complement the trend, investments by pharma companies are also rising by large bounds in those years.

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The study on the cell and gene therapy clinical trials offers deep expounding of current and emerging business strategies, elements of competition, facets of markets attractiveness, and insights into regional growth dynamics across the globe.

Cell And Gene Therapy Clinical Trials Market: Key Trends

Clinical trials pertaining to advanced therapy medicinal product (ATMP) are making consistent increase in some developed nations. A predominant percentage of these in recent years have been viral vector mediated gene therapies. Thus far, some remarkable strides have been witnessed in this direction, enriching the investment scope in the cell and gene therapy market. The effect has been notices in all phases, from Phase I to Phase IV.

A prevalent trend over the past few years is the focus on oncology. Oncology--notably including haematological malignancies and solid tumourshave been at the center of ATMP clinical trials. Metabolic disease trials have also seen a significant increase, cementing revenue growth in the cell and gene therapy market. Advances made in gene therapy trials continue to pave way to new vistas for oncology research, both in vivo and in vitro.

Cell And Gene Therapy Clinical Trials Market: Competitive Dynamics and Key Developments

The profound potential of cell and gene therapies (CGT) notwithstanding, their successful clinical translation is, no doubt, rests on panoply of problems. These also determine the key restraints for the evolution of the cell and gene therapy market. The high degree of personalization that CGT entails, factors affecting their efficacy and safety are difficult to ascertain, if not impossible. For one, obtaining cells from donors is replete with some unique challenges, such as invasiveness of the process to patients. So are the lack of availability of cutting-edge biomarkers and targets anchored on which gene therapies will show their potential. The whole process of delivering CGT in clinical trials is itself associated with some tall challenges for contract research organizations.

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Having put these perspectives, the prospects have limitless potential waiting to be extracted, and researchers are not disheartened by the aforementioned challenges. In oncology alone, a number of new approaches have added liveliness to CGT clinical trials. Biotech companies are testing new waters in allogeneic therapies. T-cell receptor (TCR) are increasingly penetrating safety and feasibility trials, adding momentum to the cell and gene therapy market.

Some of the industry players likely to invade the space of these limitless possibilities are;

Cell And Gene Therapy Clinical Trials Market: Regional Assessment

North America has been at the cynosure of attention for CGT trials. European nations have also been showing substantial potential for generating revenues in the global market. In coming years, Asia Pacific is expected to show high growth potential

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Cell And Gene Therapy Clinical Trials Market in 2021 | Expansive Coverage on the Latest Developments in the Market - BioSpace

1Department of Orthopedics, The 923rd Hospital of the Joint Logistics Support Force of the Peoples Liberation Army, Nanning, Peoples Republic of China; 2Department of Orthopedics, Peoples Hospital of Guilin, Guilin, Guangxi, 541001, Peoples Republic of China; 3Department of Orthopedics, Fifth Clinical Medical College, Guilin Medical University, Guilin, Guangxi, 541001, Peoples Republic of China; 4Department of Orthopedics, The Tenth Peoples Hospital of Nanning, Nanning, Guangxi, 530105, Peoples Republic of China

Correspondence: Bo LvPeoples Hospital of Guilin, 12 Wenming Road, Guilin, Guangxi, 541001, Peoples Republic of ChinaTel +867738997962Email [emailprotected]

Purpose: Osteosarcoma is the most common malignant bone cancer affecting adolescents and young adults. This study aimed to screen potential diagnostic and therapeutic markers for osteosarcoma.Methods: Differential expression analysis between osteosarcoma and control was performed in GSE99671, the differentially expressed genes (DEGs) were subjected to co-expression analysis. Enrichment analysis was employed to identify the biological functions and KEGG signaling pathways of module genes. In addition, a differential analysis was also performed between recurrent and non-recurrent osteosarcoma samples in GSE39055, and enrichment analysis was performed for DEGs. Further, KaplanMeier curve analysis was performed on the module genes, and receiver operating characteristic (ROC) curve was drawn. Comparison of the module with the highest correlation to osteosarcoma identified key genes. Cox regression model was utilized to identify the predictive ability of key genes for the prognosis of osteosarcoma.Results: A total of 13 co-expression modules were identified from 4871 DEGs of GSE99671, module 1 had the highest positive correlation with osteosarcoma. Module genes were mainly enriched in autophagy and macrophage migration functions. A total of 1126 DEGs were obtained from GSE39055, significantly involved in neutrophil mediated immunity. Screening of genes with area under the ROC curve (AUC) values greater than 0.73 in both GSE99671 and GSE39055 identified 5 key genes when compared with genes from module 1. The nomogram results showed that ATF5, CHCHD8, ENOPH1, and LOC286367 might predict 5-year or 8-year survival time of osteosarcoma patients. The Cox model results confirmed that the signals of ATF5, CHCHD8, and LOC286367 were robust, and it may be used in the diagnosis, treatment, and prognosis of osteosarcoma.Conclusion: We found that ATF5, CHCHD8, and LOC286367 can effectively identify osteosarcoma tumorigenesis and even recurrence status. This is helpful for early diagnosis and treatment, improving the clinical treatment of patients with osteosarcoma.

Keywords: osteosarcoma, predictive biomarkers, recurrence, weighted co-expressed network analysis

Osteosarcoma is the most common primary bone malignancy, mainly affecting children and young adults.1 Osteosarcoma consists of malignant osteoblasts producing immature bone and bone tissue.2 Although standard treatment with surgical resection and adjuvant chemotherapy has significantly improved the 5-year survival rate of osteosarcoma patients to approximately 6070%, no significant progress has been made in improving the survival rate of patients with recurrence or metastasis over the past 30 years.3,4 The lack of understanding of the molecular mechanisms underlying the occurrence and recurrence of osteosarcoma has severely hampered improved patient survival. When diagnosed, 40% of metastases occur in patients with advanced osteosarcoma.5 Therefore, elucidating the functions of osteosarcoma-related genes and exploring the possible pathological mechanisms of osteosarcoma initiation, development and recurrence are crucial for the future detection and treatment of osteosarcoma.

Depending on the histological morphology, three main categories can be distinguished: high-grade, which includes most subtypes, and intermediate and low-grade, which include periosteal and periosteal.6 Conventional osteosarcoma refers to high-grade tumors with intramedullary growth and is the most common type, accounting for 85% of all osteosarcoma cases during childhood and adolescence.7 The osteosarcoma tumor microenvironment is composed of osteosarcoma cells, osteocytes, stromal cells, vascular cells, immune cells, and the extracellular matrix (ECM).8 This creates a complex environment for tumor growth. More immune infiltration is found in osteosarcoma tumors to promote a local immune tolerant environment.9 Given the close connection between bone tissue and the immune system, it has been speculated that osteosarcoma may use similar mechanisms to evade immune recognition.10

With the development of molecular biology technology, tumor gene therapy for osteosarcoma has potential clinical applications.11,12 Accumulating evidence indicates that the occurrence, development and prognosis of osteosarcoma are closely related to molecular mechanisms.13,14 Through high-throughput sequencing, gene expression in osteosarcoma can be compared to normal samples, leading to an initial selection of potential targets for anticancer therapy.15 This also includes some common long non-coding RNAs (lncRNAs).16

This study aimed to discover the occurrence- or recurrence-related potential markers according to the osteosarcoma-related gene expression profiles in Gene Expression Omnibus (GEO) database. Multiple differentially expressed genes (DEGs) were screened using the weighted gene co-expression network analysis (WGCNA) algorithm. The main signaling pathways of osteosarcoma were analyzed by Gene Ontology (GO), function and Kyoto Encyclopedia of genes (KEGG) pathways. Subsequently, KaplanMeier and Cox models were utilized to screen the key genes related to the prognosis of osteosarcoma. The findings may provide new biomarkers and therapeutic target molecules for the occurrence and recurrence of osteosarcoma.

Osteosarcoma data were collected from the gene expression omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo) databases. GSE99671 included mRNA expression profiling of fresh-frozen bone samples from 18 tumoral samples and 18 non-tumoral paired samples by high throughput sequencing.17,18 The raw data were standardized and normalized through R package DEseq2;19 then, the gene expression profile was provided in Table S1. GSE39055 included mRNA expression profiling of formalin-fixed, paraffin-embedded (FFPE) samples from 37 unique diagnostic biopsy specimens of osteosarcoma with (n=18) or non-recurrence (n=19) by array.20 Expression data were processed using the R package lumi21 and provided in Table S2. All data were obtained from an open-access database, thus, acquiring ethical approval was not necessary.

Next, the DEseq2 package was used to identify differentially expressed genes (DEGs) in osteosarcoma (n = 18) and healthy controls (n = 18) in GSE99671 data. The limma package22 was used to screen DEGs between the recurrent osteosarcoma and non-recurrent osteosarcoma in GSE39055 data. P < 0.05 was set as the screening condition. The expression of DEGs was visualized with volcano plots.

The coexpression network for DEGs in GSE99671 was performed using Weighted correlation network analysis (WGCNA) by WGCNA R package.23 The samples were used to construct scale-free topology networks, and all gene adjacencies were calculated to make a topological overlap matrix (TOM). The soft-thresholding power was chosen and used as the correlation coefficient threshold. Then, a minimum number of genes in the modules were built. The expression pattern of eigengene in each module is condensed into module eigengene (ME). Genes in MEs were considered had similar expression patterns. The moduletrail relationships were demonstrated using Pearson correlation analysis.

The biological process (BP) in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for module genes or DEGs in GSE39055 were performed using R software package clusterProfiler.24 Gene set variation analysis (GSVA) was carried out using the GSVA package.25 For each sample, a score for the enrichment of a set of genes using gene expression profile was obtained. A P value < 0.05 was considered statistical significance. The R package clusterProfiler was used to obtain the background set for gene set enrichment analysis (GSEA). GSEA runs in Java environment and conducted between osteosarcoma and control samples.

KaplanMeier (K-M) survival analysis with the R package survival was applied to identify overall survival (OS) associated genes among the module genes. Prognostic relevant genes among the key genes were determined using Cox regression analysis in a survival package based on gene expression values and survival status data. P < 0.05 was considered to be a statistically significant difference. Based on the correlation coefficients of the risk model, a formula for calculating the prognostic risk score for each patient was established. According to the median value of the risk score, patients were divided into high- and low-risk groups.

To evaluate whether the identified survival-related genes have significant diagnostic value for osteosarcoma or recurrent osteosarcoma, we performed ROC analysis using the R software package pROC.26 The area under the ROC curve (AUC) was calculated for each gene. The diagnostic accuracy of key biomarkers was evaluated using AUC values. Here, this gene can distinguish osteosarcoma from healthy individuals or recurrent osteosarcoma from non-recurrent osteosarcoma when the AUC value is greater than 0.6.

The marker gene expression information for immune cell types was obtained by Bindea et al.27 The infiltration scores of immune cells were calculated using ssGSEA in GSVA R software package. Correlations between immune cells and key genes were calculated using Pearson correlation. P value <0.05 was considered significant.

The flowchart of this study is shown in Figure 1. To identify differences in gene expression between osteosarcoma and controls, we performed a differential analysis of the osteosarcoma and control groups in GSE99671. Using threshold screening, we obtained 4871 differentially expressed genes (DEGs) between osteosarcoma and controls (Figure 2A). The co-expression behaviors of these genes were identified by performing WGCNA on the DEGs. To ensure that the coexpression network could obey the scale-free criterion, we selected = 9 as a soft-thresholding (Figure 2B). We identified a total of 13 coexpression modules (Figure 2C). Pearson correlation analysis showed that MEturquoise (M1) had the highest positive correlation with osteosarcoma (Figure 2D).

Figure 1 The flowchart of this study. The GSE99671 data and GSE39055 data were used to identify potential biomarkers related to the occurrence and recurrence of osteosarcoma. The module genes identified in GSE99671 were used to evaluate their prognostic and diagnostic value in GSE39055. Further screening of key genes may be a target for diagnosis and treatment of osteosarcoma.

Abbreviations: WGCNA, weighted gene co-expression network analysis; GSEA, gene set enrichment analysis; ROC, receiver operating characteristic curve; AUC, area under the ROC curve.

Figure 2 Coexpression modules of differentially expressed genes. (A) The differentially expressed genes between osteosarcoma and controls in GSE99671. (B) The scale-free fit index and the mean connectivity for various soft-thresholding powers. (C) Common genes were identified for thirteen coexpression modules by WGCNA. (D) Correlations between modules and clinical trait were analyzed by Pearson correlation.

To identify the biological roles of module genes, we performed enrichment analysis. It was found that module genes were significantly enriched in activated positive regulation of macrophage migration, chaperone mediated autophagy, MHC protein complex assembly biological processes; and inhibited neutrophil aggregation, regulation of vascular permeability, regulation of cell killing in osteosarcoma (Figure 3A). Using KEGG enrichment results, we found that activated HIF-1 signaling pathway, PI3K-Akt signaling pathway, and autophagy animal were significantly enriched by module genes, and inhibited B cell receptor signaling pathway, Rap1 signaling pathway, and ECM receptor interaction were also significantly enriched in osteosarcoma (Figure 3B). GSEA results showed that protein export, RNA polymerase, and proteasome were significantly enriched in osteosarcoma, primary immunodeficiency, PPAR signaling pathway, and neutrophil extracellular trap formation were significantly enriched in control samples (Figure 3C).

Figure 3 Biological functions of module gene enrichment. (A) Module genes significantly enriched for activated and inhibited biological processes. (B) Module genes significantly enriched for activated and inhibited KEGG pathway. (C) The activated and inhibited KEGG pathways in GSEA of module genes involved. P < 0.05 was considered statistically significant.

Abbreviation: GSVA, gene set variation analysis.

To identify molecular alterations associated with osteosarcoma recurrence, we performed a differential analysis of recurrent and non-recurrent osteosarcoma gene expression in GSE39055. A total of 1126 differentially expressed genes were obtained (Figure 4A). In GO enrichment results, the activated neutrophil mediated immunity, skeletal muscle fiber differentiation, response to iron (III) ion and inhibited neutrophil apoptotic process, leukocyte homeostasis, mitochondrial organization were significantly enriched by differentially expressed genes (Figure 4B). KEGG enrichment results identified that the differentially expressed genes were significantly involved in the activated endocrine resistance, oxidative phosphorylation, renin angiotensin system; and inhibited p53 signaling pathway, cell cycle, FOXO signaling pathway in recurrent osteosarcoma (Figure 4C).

Figure 4 The potential molecular changes in osteosarcoma recurrence. (A) Volcano plot of differentially expressed genes between recurrent osteosarcoma and non-recurrent osteosarcoma. Red for activated and green for inhibited. The four genes with the largest fold change of activated or inhibited were labeled. (B) Differentially expressed genes involved in activated and inhibited biological processes quantified by gene set variation analysis (GSVA). The longer the column, the more genes involved in this term. (C) Differentially expressed genes involved in activated and inhibited KEGG pathway quantified by gene set variation analysis (GSVA). The longer the column, the more genes involved in this term.

Abbreviation: BP, biological processes.

From the survival information of 37 osteosarcoma patients obtained from GSE39055, we found that the patients 5-year overall survival (OS) was 35% (Figure 5A). The survival probability increased per year already survival related to the total survival time. To identify key genes involved in the prognosis of osteosarcoma, we performed KM curve analysis of module genes. Among the module genes, we identified 262 genes that significantly affected osteosarcoma survival. By plotting the ROC curves of these survival-related genes, we screened for genes with AUC values greater than 0.73 in both GSE99671 and GSE39055 (Figure 5B). Including AEBP1, ATF5, CHCHD8, DYRK3, ENOPH1, GMIP, LOC286367, PKP4, R3HDM1, TRIM66, and ZMYND17. They were also differentially expressed genes in GSE39055 and thus may predict both osteosarcoma occurrence and recurrence. In addition, five genes (ATF5, CHCHD8, ENOPH1, LOC286367, and R3HDM1) were identified as potentially most strongly associated with osteosarcoma by contrasting with the gene for module 1. They were identified as key genes. Nomograms were constructed using Cox regression analysis results, and differential expression of ATF5, CHCHD8, ENOPH1, and LOC286367 could predict 5 - and 8-year OS of osteosarcoma patients (Figure 5C).

Figure 5 Screening of key genes predicting the occurrence and recurrence of osteosarcoma. (A) KaplanMeier estimates for conditional survival up to 6 years in 37 patients given 05 years survival of osteosarcoma. Each column represents the survival time, and each row represents the percentage reaching the specified survival time. (B) On the left are survival associated genes with AUC values in GSE99671 and GSE39055 and on the right are genes with AUC values greater than 0.73 in both datasets. Red represents up-regulated expression and blue represents down regulated expression. The length of the column represents the mean AUC value. (C) Nomogram for the prediction of overall survival to achieve 5-year or 8-year survival time.

Abbreviation: AUC, area under the ROC curve.

On the other hand, osteosarcoma patients in GSE39055 were divided into high-risk and low-risk groups according to the median risk score which calculated by the Cox model (Figure 6A). The expressions of key genes in the high-risk and low-risk groups were different. Patients with death status were significantly higher in the high-risk group than in the low-risk group. In addition, we calculated the correlation of key genes and immune cells, LOC286367 was positively correlated with most immune cells, other key genes were negatively correlated with more immune cells (Figure 6B). The prediction capability of the key genes was evaluated by calculating the area under the ROC curve (AUC). The AUC values of ATF5, CHCHD8, and LOC286367 for predicting OS were greater than 0.6 in the first, third, and fifth year of osteosarcoma, indicating that they had good performance (Figure 6C). High expression of ATF5, CHCHD8, and LOC286367 was associated with the worst OS in osteosarcoma patients (Figure 6D). ATF5, CHCHD8, and LOC286367 were expressed at significantly higher levels of osteosarcoma compared with the normal group in GSE99671 (Figure 6E).

Figure 6 Diagnostic role of key genes predicting the survival of osteosarcoma. (A) Distribution of risk score, overall survival, and overall survival status and heatmap of the five key genes in the GSE39055. (B) Correlations between immune infiltrating cells and key genes were calculated using Pearson. *P < 0.05, **P < 0.01. (C) Time-dependent ROC curves measuring the predictive value of key genes in GSE39055 for 3-year, 5-year or 10-year survival time. (D) Effect of key genes expression on overall survival by KaplanMeier analysis in 37 patients with osteosarcoma. (E) The expression levels of ATF5, CHCHD8, and LOC286367 in osteosarcoma and normal of GSE99671. ***P < 0.001.

Abbreviation: OS, overall survival.

Osteosarcoma is one of the most common aggressive bone tumors and is currently treated with chemical drugs combined with surgical resection. A major unsolved problem is the poor prognosis characterized by drug resistance, recurrence and metastasis.28 The identification of gene signatures is crucial both for a better understanding of the molecular basis of osteosarcoma progression and for the discovery of novel targets.29 In the present study, we focused on the potential target genes with prognostic value for osteosarcoma. Gene expression profiling of differentially expressed genes detected by GSE99671 in osteosarcoma tissue samples established 13 coexpression modules. Module genes were mainly enriched in immune, inflammatory and metabolic responses. In the gene co-expression network, module 1 was most significantly associated with osteosarcoma, in which genes significantly affecting survival may be potential target genes. Furthermore, combining GSE39055, we identified 5 key genes that may serve as diagnostic markers for the occurrence and recurrence of osteosarcoma. Finally, high expression of ATF5, CHCHD8, and LOC286367 was associated with worse prognosis in osteosarcoma.

WGCNA is a systems biology approach that describes correlation patterns between genes in transcriptome samples with soft threshold algorithms.23 The results of GO and KEGG pathway enrichment analysis of the module genes led us to focus on the biological functions of autophagy and macrophage migration, as well as the HIF-1 signaling pathway and PI3K-Akt signaling pathway. Autophagy promotes the proliferation and development of osteosarcoma cells and resists tumor treatment.30 Autophagy may be involved in drug sensitivity or chemoresistance during osteosarcoma treatment.31 Macrophages are an important immune component in the osteosarcoma microenvironment. Macrophages are highly plastic and the inflammatory phenotype (M1) and anti-inflammatory phenotype (M2) may play opposite roles in the progression of osteosarcoma.32 Activation of the HIF-1 signaling pathway promotes osteosarcoma cell growth and is a promising therapeutic target.33 Accumulating evidence suggests that the PI3K/Akt pathway is involved in cancer initiation and progression, such as tumorigenesis, apoptosis inhibition, proliferation and drug resistance.34

To further identify the underlying molecular mechanisms of osteosarcoma recurrence, we performed enrichment analysis of the differentially expressed genes between recurrence and non-recurrence. We found multiple immune related pathways, neutrophil mediated immunity, neutrophil apoptotic process, and leukocyte homeostasis. They may be associated with metastasis and recurrence of osteosarcoma.35 In addition to a large number of aberrant biological functions, FOXO could control the expression of genes involved in cell death and cell cycle arrest, exerting tumor suppressor activity.36 Tumor suppressor p53 tumor cells have been reported to exert anticancer effects by inducing cell cycle arrest and apoptosis.37

Of the 13 coexpression modules we identified, module 1 was found to be strongly associated with osteosarcoma. Among the module genes identified to be significantly associated with OS of osteosarcoma, 11 genes were screened with high specificity and sensitivity as potential molecular markers for predicting the occurrence and recurrence of osteosarcoma. Among them, 5 genes were genes in module 1 and were considered as key genes. In the Cox regression model, high expression of CHCHD8 or ENOPH1 may benefit the prognosis of osteosarcoma patients, and low expression of ATF5 or LOC286367 may prolong patient survival. However, the K-M curve results differed from the Cox analysis results in that patients with low expression of the CHCHD8 gene had better overall survival. The risk assessment model constructed by 5 key genes clearly distinguished the status of osteosarcoma survival and death. Based on the time-dependent ROC curves results, we identified ATF5, CHCHD8, and LOC286367 as potential diagnostic and prognostic biomarkers for clinical outcome prediction. ATF5 is considered an anti-apoptotic factor because it regulates the expression of the anti-apoptotic components BCL2 and MCL1.38 Studies have reported ATF5 to promote tumor growth and survival and have been reported to be associated with recurrence of osteosarcoma.39,40 CHCHD8 has been reported to be associated with drug resistance in gastric cancer, but the association with osteosarcoma has not been reported.41 LOC286367 was reported to be associated with inflammatory response,42,43 the results of our analysis argued that it may be a potential marker for the occurrence and recurrence of osteosarcoma.

However, the present study has certain limitations. The first and most important is the lack of experimental validation. Second, the lack of detailed clinical data, such as chemotherapy regimens and tumor stages, limits in-depth association analyses. Finally, whether the biomarkers we identified can be applied in the clinic also needs a large number of samples to validate, which will be the focus of our future studies.

The present study identified potential diagnostic markers and useful therapeutic targets for osteosarcoma patients, and they may be able to predict patient prognosis. The mechanism of recurrence of osteosarcoma may be associated with neutrophil immunity and cell cycle arrest. In-depth exploration of the potential target genes and molecular deregulation mechanisms to develop corresponding prevention and treatment countermeasures can achieve breakthrough progress in the prognosis of osteosarcoma.

Data were downloaded from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/).

This study was supported by the Scientific Research Project of Guangxi Health Commission (Z20180799).

The authors report no conflicts of interest related to this work.

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Identification of Gene as Predictive Biomarkers for the Occurrence and | IJGM - Dove Medical Press

-Collaboration brings together breakthrough gene editing technology and leading natural killer (NK) cell and T cell discovery, development, and manufacturing capabilities-

-Companies to co-develop and co-commercialize two chimeric antigen receptor (CAR) NK cell product candidates, one targeting CD70, and a product candidate combining NK and T cells (NK+T)-

-Nkarta obtains a license to CRISPR gene editing technology for use in its own engineered NK cell therapy products-

-Nkarta to host conference call today at 4:30 p.m. ET-

ZUG, Switzerland, CAMBRIDGE, Mass., and SOUTH SAN FRANCISCO, Calif., May 06, 2021 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (NASDAQ: CRSP), a biopharmaceutical company focused on developing transformative gene-based medicines for serious diseases, and Nkarta, Inc. (NASDAQ: NKTX), a biopharmaceutical company developing engineered NK cell therapies to treat cancer, today announced a strategic partnership to research, develop, and commercialize CRISPR/Cas9 gene-edited cell therapies for cancer.

Under the agreement, the companies will co-develop and co-commercialize two CAR NK cell product candidates, one targeting the CD70 tumor antigen and the other target to be determined. In addition, the companies will bring together their complementary cell therapy engineering and manufacturing capabilities to advance the development of a novel NK+T product candidate harnessing the synergies of the adaptive and innate immune systems. Finally, Nkarta obtains a license to CRISPR gene editing technology to edit five gene targets in an unlimited number of its own NK cell therapy products.

CRISPR Therapeutics and Nkarta will equally share all research and development costs and profits worldwide related to the collaboration products. For each non-collaboration product candidate incorporating a gene editing target licensed from CRISPR Therapeutics, Nkarta will retain worldwide rights and pay CRISPR Therapeutics milestones and royalties on net sales. The agreement includes a three-year exclusivity period between CRISPR Therapeutics and Nkarta covering the research, development, and commercialization of allogeneic, gene-edited, donor-derived NK cells and NK+T cells.

By bringing together CRISPR Therapeutics and Nkartas highly complementary expertise and proprietary platforms we plan to accelerate the development of potentially groundbreaking genome engineered NK cell therapies, said Samarth Kulkarni, Ph.D., Chief Executive Officer at CRISPR Therapeutics. This collaboration broadens the scope of our efforts in oncology cell therapy, and expands our efforts to discover and develop novel cancer therapies for patients.

Uniting the best-in-class gene editing solution and allogeneic T cell therapy expertise of CRISPR with Nkartas best-in-class CAR NK cell therapy platform will be a major advantage to advancing the next wave of transformative cancer cell therapies, said Paul J. Hastings, President and Chief Executive Officer of Nkarta. With this partnership, Nkarta can systematically apply world-class gene editing across our entire pre-clinical pipeline going forward. CRISPRs deep understanding of CD70 biology and experience in allogeneic T cell clinical development can accelerate the development of early-stage Nkarta programs, to deliver innovative treatments to patients that much faster.

Nkarta Conference Call DetailsNkarta management will host a conference call to discuss the collaboration today at 4:30 p.m. Eastern Time (ET). The event will be simultaneously webcast and available for replay from the Nkarta website at http://www.nkartatx.com, under the Investors section. Investors may also participate in the conference call by calling 877-876-9174 (domestic) or +1-785-424-1669 (international). The conference ID is NKARTA.

AboutCRISPR TherapeuticsCRISPR Therapeuticsis a leading gene editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a revolutionary gene editing technology that allows for precise, directed changes to genomic DNA.CRISPR Therapeuticshas established a portfolio of therapeutic programs across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine and rare diseases. To accelerate and expand its efforts,CRISPR Therapeuticshas established strategic collaborations with leading companies includingBayer, Vertex PharmaceuticalsandViaCyte, Inc.CRISPR Therapeutics AGis headquartered inZug, Switzerland, with its wholly-ownedU.S.subsidiary,CRISPR Therapeutics, Inc., and R&D operations based inCambridge, Massachusetts, and business offices inSan Francisco, CaliforniaandLondon, United Kingdom. For more information, please visitwww.crisprtx.com.

CRISPR THERAPEUTICS word mark and design logo are registered trademarks ofCRISPR Therapeutics AG. All other trademarks and registered trademarks are the property of their respective owners.

CRISPR Therapeutics Forward-Looking StatementThis press release may contain a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements made by Dr. Kulkarni and Mr. Hastings in this press release, as well as statements regarding CRISPR Therapeutics expectations about any or all of the following: (i) the future activities of the parties pursuant to the collaboration and the expected benefits of CRISPR Therapeutics collaboration with Nkarta; and (ii) the therapeutic value, development, and commercial potential of CRISPR/Cas9 gene editing technologies and therapies. Without limiting the foregoing, the words believes, anticipates, plans, expects and similar expressions are intended to identify forward-looking statements. You are cautioned that forward-looking statements are inherently uncertain. Although CRISPR Therapeutics believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: CRISPR Therapeutics may not realize the potential benefits of the collaboration, uncertainties inherent in the initiation and completion of preclinical studies; availability and timing of results from preclinical studies; whether results from a preclinical study will be favorable and predictive of future results of future studies or clinical trials; uncertainties about regulatory approvals and that future competitive or other market factors may adversely affect the commercial potential for product candidates; potential impacts due to the coronavirus pandemic, such as the timing and progress of preclinical studies; uncertainties regarding the intellectual property protection for CRISPR Therapeutics technology and intellectual property belonging to third parties, and the outcome of proceedings (such as an interference, an opposition or a similar proceeding) involving all or any portion of such intellectual property; and those risks and uncertainties described under the heading "Risk Factors" in CRISPR Therapeutics most recent annual report on Form 10-K, quarterly report on Form 10-Q, and in any other subsequent filings made by CRISPR Therapeutics with the U.S. Securities and Exchange Commission, which are available on the SEC's website at http://www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. CRISPR Therapeutics disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this press release, other than to the extent required by law.

About Nkartas NK Cell TechnologiesNkarta has pioneered a novel discovery and development platform for the engineering and efficient production of allogeneic, off-the-shelf natural killer (NK) cell therapy candidates. The approach harnesses the innate ability of NK cells to recognize and kill tumor cells. To enhance the inherent biological activity of NK cells, Nkarta genetically engineers the cells with a targeting receptor designed to recognize and bind to specific proteins on the surface of cancerous cells. This receptor is fused to co-stimulatory and signaling domains to amplify cell signaling and NK cell cytotoxicity. Upon binding the target, NK cells become activated and release cytokines that enhance the immune response and cytotoxic granules that lead to killing of the target cell. All of Nkartas NK current cell therapy candidates are also engineered with a membrane-bound IL15, a proprietary version of a cytokine known for activating NK cell growth, to enhance the persistence and activity of the NK cells.

Nkartas manufacturing process generates an abundant supply of NK cells that, at commercial scale, is expected to be significantly lower in cost than other current allogeneic and autologous cell therapies. Key to this efficiency is the rapid expansion of donor-derived NK cells using a proprietary NKSTIM cell line, leading to the production of hundreds of individual doses from a single manufacturing run. The platform also features the ability to freeze and store CAR NK cells for an extended period of time and is designed to enable immediate, off-the-shelf administration to patients at the point of care.

About NkartaNkarta is a clinical-stage biotechnology company advancing the development of allogeneic, off the shelf natural killer (NK) cell therapies for cancer. By combining its cell expansion and cryopreservation platform with proprietary cell engineering technologies, Nkarta is building a pipeline of cell therapy candidates generated by efficient manufacturing processes, which are engineered to enhance tumor targeting and improve persistence for sustained activity in the body. For more information, please visit http://www.nkartatx.com.

Nkarta, Inc. Cautionary Note on Forward-Looking StatementsStatements contained in this press release regarding matters that are not historical facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Words such as "anticipates," "believes," "expects," "intends," plans, potential, "projects, would and "future" or similar expressions are intended to identify forward-looking statements. Examples of these forward-looking statements include statements concerning: Nkartas expectations regarding its ability to advance the development and commercialization of two gene-edited CAR-NK cell therapies and an NK+T cell therapy under the collaboration with CRISPR Therapeutics, and the ability of Nkarta and CRISPR Therapeutics to leverage the combination of their respective expertise and platforms to accelerate that development; Nkartas application of gene-editing across its preclinical pipeline; the ability of Nkartas technology to enhance the persistence and anti-tumor activity of NK cells and enable off-the-shelf, point-of-care administration; the efficiency and cost of Nkartas manufacturing processes; the number of doses generated from a manufacturing run; and the proprietary nature of Nkartas technology. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. These risks and uncertainties include, among others: Nkartas limited operating history and historical losses; Nkartas ability to raise additional funding to complete the development and any commercialization of its product candidates; Nkartas dependence on the success of its co-lead product candidates, NKX101 and NKX019; that Nkarta may be delayed in initiating, enrolling or completing any clinical trials; competition from third parties that are developing products for similar uses; Nkartas ability to obtain, maintain and protect its intellectual property; Nkartas dependence on third parties in connection with manufacturing, clinical trials and pre-clinical studies; the complexity of the manufacturing process for CAR NK cell therapies; and risks relating to the impact on Nkartas business of the COVID-19 pandemic or similar public health crises.

These and other risks are described more fully in Nkartas filings with the Securities and Exchange Commission (SEC), including the Risk Factors section of Nkartas Annual Report on Form 10-K for the year ended December 31, 2020, filed with the SEC on March 25, 20201, and our other documents subsequently filed with or furnished to the SEC. All forward-looking statements contained in this press release speak only as of the date on which they were made. Except to the extent required by law, Nkarta undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

CRISPR Therapeutics Investor Contact:Susan Kim+1-617-307-7503susan.kim@crisprtx.com

CRISPR Therapeutics Media Contact:Jennifer PaganelliReal Chemistry on behalf of CRISPR+1-347-658-8290jpaganelli@realchemistry.com

Nkarta Media/Investor Contact:Greg MannNkarta, Inc.+1-415-317-3675gmann@nkartatx.com

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CRISPR Therapeutics and Nkarta Announce Global Collaboration to Develop Gene-Edited Cell Therapies for Cancer - GlobeNewswire

Most people on Earth are genetically more similar than different; however, small differences are important in respect of how experts understand complex diseases.

First published in the Daily Maverick 168 weekly newspaper.

The largest genetic study ever undertaken of South Africans has challenged the presumption that all southeastern Bantu-speaking groups are a single genetic entity and this has a huge implication for the study of diseases.

The southeastern Bantu language family includes isiZulu, isiXhosa, siSwati, Xitsonga, Tshivenda, Sepedi, Sesotho and Setswana. Despite linguistic differences, these groups of people are treated mostly as a single group in genetic studies.

Almost 80% of South Africans speak one of the southeastern Bantu languages as their first language. Their origins can be traced to farmers of west central Africa, whose descendants over the past 2,000 years spread south of the equator and into southern Africa.

Professor Michle Ramsay, director of the Sydney Brenner Institute for Molecular Bio-science at the University of the Witwatersrand University (Wits) and the corresponding author of the study, said to investigate this, the largest study with genome-wide genotyping in South African populations was undertaken with 5,000 participants. This is a very detailed analysis of genetic markers across the whole genome.

The research, published in the journal Nature Communications, was carried out by a multidisciplinary team of geneticists, bioinformaticians, linguists, historians and archaeologists at Wits University, including Ramsay, Dhriti Sengupta, Ananyo Choudhury, Scott Hazelhurst, Shaun Aron and Gavin Whitelaw, along with experts at the University of Limpopo and partners in Belgium, Sweden and Switzerland.

The archaeological record and rock art evidence trace the presence of a San-like hunter-gatherer culture in southern Africa to at least 20,000 to 40,000 years ago.

Three sets of migration events have dramatically reshaped the genetic landscape of this geographic region in the last two millennia. The first of these was a relatively small-scale migration of east African pastoralists, who introduced pastoralism to southern Africa about 2,000 years ago. This population was subsequently assimilated by local southern African San hunter-gatherer groups, forming a new population that was ancestral to the Khoekhoe herder populations.

Today, southern African Khoe and San populations collectively refer to hunter-gatherer (San) and herder (Khoekhoe) communities. While Khoe-San groups are distributed over a large geographic area today (spanning the Northern Cape province of South Africa, large parts of Namibia, Botswana, and southern Angola), these groups are scattered, small and marginalised.

The introduction of pastoralism in the region was closely followed by the arrival of the second set of migrants, that is the Bantu-speaking agro-pastoralists. The archaeological record suggests that ancestors of the current-day [Bantu-speaking] populations undertook different waves of migration instead of a single large-scale movement.

The earliest communities spread along the east coast to reach the KwaZulu-Natal south coast by the mid-fifth century AD, while the final major episode of settlement is estimated to be around AD1350. These archaeologically distinct groups gradually spread across present-day South Africa, interacting to various degrees with the Khoe-San groups giving rise to South Africas diverse [Bantu-speaking] communities.

The third major movement into southern Africa was during the colonial era in the last four centuries when European colonists settled in the area. During this period slave trade introduced additional intercontinental gene flow giving rise to complex genomic admixture patterns in current-day southern African populations.

Since these migrations took place, varying degrees of sedentism (the practice of living in one place for a long time), population movements and interaction with Khoe and San communities, as well as people speaking other southeastern Bantu languages, ultimately generated what are today distinct southern African languages such as isiZulu, isiXhosa and Sesotho.

Despite these linguistic differences, these groups are treated mostly as a single group in genetic studies. Understanding genetic diversity in a population is critical to the success of disease genetic studies. If two genetically distinct populations are treated as one, the methods normally used to find disease genes could be error-prone.

Most people on Earth are genetically more similar than different; however, small differences are important in respect to how experts understand complex diseases.

Southeastern Bantu speakers have a clear linguistic division they speak more than nine distinct languages and their geography is clear: some of the groups are found more frequently in the north, some in central, and some in southern Africa. Yet despite these characteristics, the [southeastern Bantu language] groups have so far been treated as a single genetic entity, said Choudhury.

These groups are too different from each other to be treated as a single genetic unit, the research has shown.

We wanted to see whether this population sub-structure could interfere in studies on diseases susceptibility. What we showed is that if you do a study in South Africa on people who self-identify as southeastern Bantu speakers, one cannot treat them as a homogeneous group.

So, if you are treating, say, the Tsonga and the Xhosa as the same population as was often done until now you might get a completely wrong gene implicated for a disease, said Sengupta. There are not major differences, but small cumulative differences in populations that were geographically isolated for about 1,000 years and who encountered and mixed in different ways with other populations (for example the Khoe and San). Many of the differences may not have any phenotypic [observable physical traits] implications, but some may be related to markers that are associated with susceptibility to diseases, said Ramsay.

We wanted to see whether this population sub-structure could interfere in studies on diseases susceptibility. What we showed is that if you do a study in South Africa on people who self-identify as southeastern Bantu speakers, one cannot treat them as a homogeneous group.

If you are doing a case-control study to find genetic markers for association with common diseases like diabetes, cancer or hypertension, and your study cases are predominantly from people of one ethnolinguistic group and your controls are from another, you may find associations that are due to ethnic differences and not association with the disease. So you could make the wrong assumptions about what caused susceptibility to a particular disease, Ramsay added.

A common approach to identify if a genetic variant causes or predisposes a person to a disease is to take a set of individuals with a disease (such as high blood pressure or diabetes) and another set of healthy individuals without the disease, and compare the occurrence of genetic variants in the two sets. If a variant shows a notable frequency difference, it is assumed that the genetic variant could be associated with the disease.

However, this approach depends entirely on the underlying assumption that the two groups consist of genetically similar individuals. One of the major highlights of our study is the observation that Bantu-speakers from two geographic regions or two ethnolinguistic groups cannot be treated as if they are the same when it comes to disease genetic studies, said Choudhury.

The study detected major variations in genetic contribution from the Khoe and San into southeastern Bantu-speaking groups; some groups have received a lot of genetic influx from Khoe and San people, while others have had very little genetic exchange with these groups. This variation ranged on average from about 2% in Tsonga to more than 20% in Xhosa and Tswana.

The study showed that there could be substantial errors in disease gene discovery and disease risk estimation if the differences between south-eastern Bantu-speaking groups are not taken into consideration, said Sengupta.

The genetic data also show major differences in the history of these groups over the past 1,000 years. Genetic exchanges were found to have occurred at different points in time, suggesting a unique journey for each group over the past millennium.

These genetic differences are strong enough to impact the outcomes of biomedical genetic research.

Sengupta emphasised that ethnolinguistic identities are complex and cautioned against extrapolating broad conclusions from the findings: Although genetic data showed differences between groups, there was also a substantial amount of overlap. While findings regarding differences could have huge value from a research perspective, they should not be generalised, she said.

Ramsay said: We would love to expand the Southern African Human Genome Programme we started in 2011 with funding from the Department of Science and Innovation. We had ambitions to sequence 10,000 South African genomes, but there was no funding for this. It is important to consider what we want to achieve from a scientific point of view and then to assess the sample size that would be needed to achieve our goals. These same samples and their associated phenotype data are also being used to do many other studies on genetic associations with cardiometabolic diseases.

The effort is also part of the broader Human Heredity and Health in Africa (H3Africa) consortium, a collaboration between the African Society of Human Genetics, the National Institutes of Health in the US and the Wellcome Trust, to boost the study of genomics and the environmental determinants of diseases that are common among African populations.

Professor Ambroise Wonkam, director of Genetic Medicine of African Populations at the University of Cape Towns Division of Human Genetics, has a vision to work through H3Africa to sequence the genomes of three million people from across the continent. Less than 2% of all human genomes analysed to date have been those of people of African ancestry.

The reference genome sequences built from the Human Genome Project are missing many variants from African ancestral genomes. A 2019 study estimated that a genome representing the DNA of the African population would have about 10% more DNA than the current reference, he writes in Nature. DM168

This story first appeared in our weekly Daily Maverick 168 newspaper which is available for free to Pick n Pay Smart Shoppers at these Pick n Pay stores.

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How migration events have dramatically reshaped the genetic landscape of Africa - Daily Maverick

Newswise The living organism is kept alive and healthy by an intricate network of biochemical processes. These are remarkably resilient in responding to changes in the environment, but they can sometimes go wrong. A key tenet of medicine is to understand these pathways in order to treat disease more effectively.

Now a research team, led by Professor Daniel Tenen of the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS), has found a major molecular switch that controls how cells turn their genes on and off. This process ensures the cell correctly and adequately performs its assigned tasks in the body.

The scientists used hematopoietic stem cells as a case study. These are vital cells that replenish the bodys blood cells throughout life.

A cells genes are encoded in long DNA strands, which are coiled up into highly elaborate structures called chromosomes. For the correct genes to be expressed at the correct times and in correct amounts in the cell, the shape of the chromosomes must be adjusted constantly. This is done by a protein called CTCF, which binds to parts of the DNA that have a particular sequence of codes and makes a loop in the DNA that activates the necessary gene.

However, the scientists found another protein called ZF143 that controls the activity level of CTCF. This so-called zinc finger protein has a protruding molecular appendage that holds a zinc atom and gives the protein the desired chemical properties.

The scientists deactivated ZNF143 by locating and deleting its gene using molecular markers. They found that hematopoietic stem cells without ZNF143 were unable to make new blood cells. In this case, it could cause serious diseases like anaemia.

The teams findings were published in the journal Nature Communications on 4 January 2021.

Their discovery will likely improve the understanding of how normal stem cells function, and could possibly lead to insights into disease. Prof Tenen said, Findings from this study has advanced our understanding of the regulatory mechanisms of CTCF-DNA binding and gene expression. It will be of great interest to investigate whether these findings have relevance to developmental disorders and cancers.

Moving forward, the team plans to study the molecular structure of the proteins involved to further understand the process and how it can be modified.

View the full press release at: https://news.nus.edu.sg/nus-scientists-found-a-key-element-that-affects-how-genes-are-expressed-in-blood-stem-cells/

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NUS scientists found a key element that affects how genes are expressed in blood stem cells - Newswise

Theres a new autoimmune disease player in town: Esker Therapeutics has raised $70 million to work on a new, focused way that can go beyond some of the limitations of JAK1 drugs.

That series A cash comes from Foresite Capital, and, while it has some earlier programs, the main focus for now is on TYK2 inhibitor ESK-001, initially for psoriasis.

TYK2 is a gene that encodes a member of the tyrosine kinase and the well-known Janus kinases (JAKs) protein families. It is a central node in the signaling pathways of cytokines known to be key mediators of inflammation and autoimmune diseases.

In preclinical studies, Esker says its asset showed potent and highly selective TYK2 inhibition, while avoiding unwanted side effects often seen with JAKs.

This put its in the same space as Bristol Myers Squibb and its TYK2 deucravacitinib, which recently outperformed Amgens Otezla in a phase 3 clinical trial of patients with moderate to severe plaque psoriasis and is much closer to a possible approval.

RELATED: AbbVie's Rinvoq rollout on track despite JAK safety concerns, but uncertainty remains: analyst

While looking into psoriasis first, with a phase 1 now ongoing, it will hope to move beyond that into more autoimmune targets, and it hopes bring in the sort of blockbuster sales seen with older meds that have gone after the same indications, like AbbVies Humira.

Autoimmune diseases are the third most common cause of chronic illness. In the U.S. alone, they impact 25 million people and cost more than $100 billion annually, said June Lee, M.D., founder, president and CEO of Esker Therapeutics.

While a number of targeted therapies have emerged in recent decades, response rates to treatments are low, and there remains a significant need for treatments that are specific to certain patient populations and that can be tolerated over long periods of time. Our goal at Esker is to rewrite the autoimmune treatment playbook by developing the right medicine for each patient.

There is also a precision analytics platform powered by Foresite Labs that comes with the biotech. This platform comprises high-quality curated genetic, clinical and health records data, a systems immunology toolkit for prospective data collection and tools for building patient registries, according to the biotech.

Our knowledge of the central molecular players in autoimmune diseases has been greatly enhanced through insights from human genetics and systems immunology, added Vik Bajaj, Ph.D., co-founder and CEO of Foresite Labs and managing director at Foresite Capital.

This platform is already being applied to advance Eskers lead program, ESK-001, in psoriasis, and we believe its utility across autoimmune disease is far larger. We are proud to support Dr. June Lee in launching this transformative company.

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Esker Therapeutics launches with $70M and a focused approach for autoimmune diseases beyond JAKs - FierceBiotech

Guest post by Daphne Zohar, the founder and CEO of PureTech Health, a Boston-based biopharma that is advancing 26 therapeutics and therapeutic candidates through its internal pipeline and its Founded Entities, including two that have received FDA clearance and European marketing authorization.

The news ricocheted through the bio innovation community, sparking alarm and frustration.

Innovators and entrepreneurs, scientists and CEOs reacted with deep concern to the Biden administrations decision this week to support temporarily waiving intellectual property rights for COVID-19 vaccines.

This was the third time in just the past few months that politicians sought to intervene in the biopharma industry with policy proposals that betrayed a deep misunderstanding of the complex engine driving the discovery and development of life-saving and, in this case, pandemic-ending medicines.

First, Rep. Katie Porter (D-CA) released a report blasting mergers and acquisitions (M&A) in the biopharma industry. This report painted a false picture of M&A as a destructive force that supposedly squashes innovation and kills jobs. The Federal Trade Commission then announced an investigation of M&As impact on competition in the industry, spurring an investor sell-off. Actually, M&A is the lifeblood of innovation, funding startups and supporting job creation and development of new cures and bringing them to patients.

(Photo by Michael Brochstein/SOPA Images/LightRocket via Getty Images)

Next, members of Congress renewed a vocal push for legislation to control drug pricing. One proposal would authorize the federal government to impose a tax of up to 95% on the revenue from certain drugs if pharma companies refused to negotiate lower prices. This concept is ill informed and would severely limit the ability of biotech companies to attract the funding needed to advance new cures. While there are absolutely some unjustified price hikes, in many cases, costs to patients are artificially driven up by middlemen. There are much better ideas for reducing the burden of out of pocket costs on patients and their families, including insurance and rebate reform, value based pricing models, and incentives to offset costs for loss-making biotechs.

Then this past week, we have the spectacle of policy makers grabbing headlines with cries to cancel vaccine patents. Its a soundbite solution that would do nothing to address supply bottlenecks or speed near-term production. Instead, it could help our geopolitical rivals steal US technology and make it less likely that industry will jump in to save us from the next pandemic. Without protection for intellectual property, investors wont put up the huge sums, often billions, needed to take a potential cure from initial concept to proven therapy. That means no more vaccines, no more gene therapies for rare disease, no more novel treatments for cancer, Alzheimers disease and other devastating conditions.

The common thread in all these proposals is a rush to act well meaning, perhaps, but coupled with a catastrophic failure to understand the thriving ecosystem put at risk by these policies.

Its as if, having been stung by a bee at a picnic, you hired a squadron of exterminators to destroy every honeybee in the state. You wouldnt fix the problem. You would, however, disrupt a delicate ecosystem in which honeybees play a pivotal role. And the downstream consequences to the environment would be disastrous.

To be clear, Im not arguing that politicians must steer clear of any issue involving biopharma. These are the right problems to focus on and I support smart regulation and sound policy, as does most everyone I know in the industry. But its imperative that lawmakers listen.

Listen to the academic scientists who ask bold questions and run painstaking experiments that sometimes lead to discoveries which reshape our understanding of human biology.

Listen to entrepreneurs like myself who pour everything we have into shepherding those breakthrough discoveries from the lab into a medicine that will make a difference in patients lives, whether that be a novel cancer immunotherapy or a therapy that could potentially address the lung scarring of Long COVID.

Listen to the investors who risk huge sums to back audacious visions: Gene editing to conquer heart disease, mRNA vaccines, or living biotherapeutics to tackle autoimmune diseases. These are technologies you dont know about until they make it through decades of discovery, research, and clinical development. Then you cant imagine modern medicine without them.

Listen, above all, to the patients and their families, many of them living in pain and fear, waiting and praying for new therapies to reach them.

While Im proud to be a biopharma CEO, Ill be the first to say that the industry isnt perfect. Thats why we need smart regulation. But like good medicines, smart policies require a deep understanding of the ecosystem youre trying to modulate.

There are many of us on the frontlines of drug discovery and bio-entrepreneurship who would be happy to work together on smart policies. Well explain the challenges we face and the benefits that flow from our unique ecosystem which nurtures innovation, promotes growth, supports millions of jobs and brings life-saving medicines to market.

Dont let policy-by-soundbite kill the engine that brought you COVID vaccines with 95% efficacy, cures for hepatitis C, and hope for people living with cancer and rare diseases. The world depends on the innovation we nurture. Dont act until you understand it.

Excerpt from:
Congress, These Are The Right Problems But The Wrong Solutions. Dont Make The Mistake Of Killing The Innovation That Brings New Medicines And Jobs. -...

PHILADELPHIA, May 5, 2021 /PRNewswire/ --When Luke Terrio was about seven months old, his mother began to realize something was off. He had constant ear infections, developed red spots on his face, and was tired all the time. His development stagnated, and the antibiotics given to treat his frequent infections stopped working. His primary care doctor at Children's Hospital of Philadelphia (CHOP) ordered a series of blood tests and quickly realized something was wrong: Luke had no antibodies.

At first, the CHOP specialists treating Luke thought he might have X-linked agammaglobulinemia (XLA), a rare immunodeficiency syndrome seen in children. However, as the CHOP research team continued investigating Luke's case, they realized Luke's condition was unlike any disease described before.

Using whole exome sequencing to scan Luke's DNA, CHOP researchers discovered the genetic mutation responsible for his condition, which prevents Luke and patients like him from making B cells and antibodies to fight infections. The study describing Luke's condition, which CHOP researchers named PU.1 Mutated agammaglobulinemia (PU.MA), was published today in the Journal of Experimental Medicine.

"It can be pretty scary for a family whose child has a mysterious illness" said Neil D. Romberg, MD, an attending physician with the Division of Allergy and Immunology at CHOP and senior author of the paper. "In this case, science provided an explanation, thanks to numerous departments at CHOP, including the Roberts Individualized Medical Genetics Center, the Center for Spatial and Functional Genomics, and the Cancer Center. Understanding the cause of Luke's condition absolutely helped us know what direction to take his therapy."

"I was so impressed with how all of the specialists at CHOP worked together as a team, even though they specialized in different areas," said Luke's mother, Michelle. "They knew something was wrong with Luke, and they didn't stop digging until they figured it out."

Figuring Out the "Why"

To pinpoint the gene at fault, CHOP researchers compared whole exome sequences from 30 patients across the globe who were born without B lymphocytes, the cells which produce antibodies. From the larger group, they identified six patients, including Luke, who had a mutation in a gene called SPI1, which encodes the PU.1 protein. PU.1 helps B lymphocytes developing in bone marrow to open up "doors" in their chromatin, a type of tightly packed DNA. Without PU.1, those door remains shut, and the B cells never form. The six PU.MA patients, who ranged in age from 15 months to 37 years, each had different SPI1 mutations but shared insufficient levels of PU.1, absent B cells and, consequently, zero antibodies.

To validate the roles of SPI1 and PU.1, the researchers used CRISPR to reconstitute the condition in vitro. Using donated cord blood of patients who lacked SPI1 mutations, the researchers employed CRISPR to edit the patients' SPI1 mutations into the donated cord blood genes. After culturing the cells for six weeks and sequencing the cells that survived, they found B cells were specifically intolerant of PU.1 changes.

Treatment Without a Playbook

Because Luke's condition was entirely new, there was no playbook for his family or his medical team to follow. After consulting with the research team, the family decided to proceed with a bone marrow transplant in the hope that the procedure would help him make his own B cells and antibodies. Soon they discovered they had a perfect match living under their own roof: Luke's older brother, Jack.

At three and a half years of age, Jack, who has high-functioning autism, donated his bone marrow to Luke. The transplant was successful at getting Luke to produce his own B cells. Until those B cells are able to create enough protective antibodies by themselves, Luke continues to receive infection protection from the antibody infusions he receives every two weeks.

"We call them his ninjas," said Michelle describing antibodies. "We tell him that he doesn't make his own ninjas, so he needs these ninja infusions to fight the germs and keep him safe."

Thanks to those "ninjas" and his brother's gift of bone marrow, Luke is now an energetic 4-year-old boy who loves Transformers, fire trucks, and his balance bike. Before his bone marrow transplant and the infusions, he needed naproxen twice a day for his joint pain, required leg braces to straighten his legs, and would lie on the floor exhausted tire after 10 minutes of activity. Now, he always seems to be running, often with his dog Charlie chasing behind him.

"Knowing the source of the problem removed the boogeyman for the Terrios and allowed them to move their lives forward," Romberg said. "Figuring out Luke's case not only helped guide his therapy and gave answers to others suffering with this rare condition in some cases for years but also opens the door to learning more about the effects of PU.1 on a variety of more common human diseases and conditions."

Le Coz et al. "Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients," Journal of Experimental Medicine, online May 5, 2021, DOI: 10.1084/jem.20201750

About Children's Hospital of Philadelphia: Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 595-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

Contact: Camillia TraviaChildren's Hospital of Philadelphia(425) 492-5007traviac@chop.edu

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SOURCE Children's Hospital of Philadelphia

Originally posted here:
CHOP Researchers Discover New Disease that Prevents Formation of Antibodies - BioSpace

Its the new rallying cry of infectious disease experts across the United States.

Get your second dose.

With nearly a third of the U.S. population now fully vaccinated, a worrisome trend has popped up, according to those experts.

Some people are choosing to take the first of the two-shot series required with both Pfizer and Moderna vaccinations but are opting out of the second shot.

The Centers for Disease Control and Prevention (CDC) reports that about 8 percent of people who have received a first shot of the two-shot vaccines have missed their second shot.

Officials are digging into the situation and speaking out about why getting both shots in the two-shot series is critical.

They say that the second dose not only builds herd immunity, but also strengthens the protection from serious COVID-19 illness and complications.

Many have the illusion they are completely protected (with one of the two shots), but they are not, Dr. William Schaffner, an infectious disease expert at Vanderbilt University School of Medicine in Nashville, Tennessee, told Healthline. Some may lose their prevention ability sooner, and they wont know it.

The first shot is priming the pump, Schaffner said, and the second dose brings up the water.

Dr. John Zaia, the director of the City of Hopes Center for Gene Therapy in the Los Angeles area and a specialist in vaccine research, told Healthline the trend of skipping second doses concerns him.

The virus and its variants, he explained, seek out hosts. That means that with more people vaccinated, the virus may hone in on those who arent fully vaccinated.

With strong variants immerging, Zaia added, he hopes to see everyone take both doses.

Dying from COVID-19, he noted, looks to be almost fully avoidable with two shots.

Zaia points to a study by a team at Houston Methodist Hospital that drilled down on the chances of both developing COVID-19 or dying from it for the fully and partially vaccinated.

In the study, which hasnt been peer reviewed yet, less than 1 percent of those who had taken both shots were hospitalized. That number jumped to more than 3 percent for those who opted for just one of the two shots.

In addition, the study found that the two-shot total dose is 98 percent effective at preventing death from COVID-19, while choosing to stop at one shot drops that down to 64 percent.

Why are people skipping a second dose?

Schaffner sees it as not one big reason but many small ones.

He points to things such as believing one shot protects them enough, fearing sickness from the second dose, preoccupation and difficulty scheduling, and COVID fatigue.

Experts say that if you received your first shot and for whatever reason didnt schedule a second, now is the time to do just that.

Its not too late, Zaia said.

According to the CDC, both the Pfizer and Moderna vaccines can be administered up to 6 weeks after the first dose.

No data is available yet on whether getting a second shot after that 6-week period is effective enough.

Zaia said a persons best plan is to get both within the time frame or as close to it as they can.

If you do decide to get the second dose, be sure to know which shot you had the first time. Most sites will ask to see your vaccination card to confirm that on site.

Schaffner hopes the public listens to the plea of infectious disease experts and rethink the second shot if theyve decided to skip it.

See more here:
Important to Get Second Dose of COVID-19 Vaccine - Healthline