Category Archives: Gene Medicine

A large new study scanned the genes of hundreds of thousands of women near the age of menopause and turned up hundreds of genetic signals that the researchers said might help predict and prevent early menopause, as well as treat infertility and improve womens reproductive health in the future.

The study, published in Nature, identified 290 genetic variants, many of them part of a pathway that repairs DNA, associated with the age at which women enter menopause. Researchers also found that changing the levels of two of these DNA repair genes delayed menopause in mice. The study broadens the understanding of how genes, specifically those in the DNA-damage response pathway, could influence the reproductive life span in women.

The average age at which women start menopause is about 51 years, and is brought on by a decrease of ovarian reserve, the capacity to produce healthy eggs. But there is significant variation in the age of menopause onset, determined by genetics and environmental factors. Although the environmental factors that influence menopause, like smoking and chemotherapy, are well-studied, the genetic factors had remained a black box.

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Studying the underlying biology and genetics of menopause has proven difficult because a womans supply of eggs are mostly formed before birth and studying it in adult humans often means taking a sample of ovarian tissue. If you were studying muscle or skin, you can take a biopsy of those tissues, said Anna Murray, a geneticist at the University of Exeter in the U.K. and author of the new study. Nobodys going to biopsy a womans ovaries its very precious tissue.

To get around these difficulties, researchers looked to genetic studies called genome-wide association studies, or GWAS. Two such previous studies had identified around 60 genetic regions associated with the timing of menopause.

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Now the multi-institutional team looked at the genes of a much larger group of women, about 200,000, between 40 and 60 years old, and found nearly 300 genetic signals associated with menopause timing. Similar to the results of their previous studies, many of the genetic regions they identified are involved in processes that respond to DNA damage to maintain cells health or induce cell death if necessary. Still, the researchers were surprised by how prevalent this pathway was in their findings. I dont know if other traits have found this level of enrichment for one particular process, said Murray.

Using the identified variants, the authors produced a risk score to see if they could predict which individuals were likely to have premature ovarian insufficiency, which occurs when women reach menopause before the age of 40. Although it was a weak predictor, the risk score identified women who started menopause by 40 better than smoking status.

Two DNA-repair genes, Chek1 and Chek2, stood out for their strong association with menopause timing. Women who lacked a working Chek2 protein had menopause three and a half years later than those who had normal Chek2, and female mice bred without the Chek2 gene had more eggs than normal mice when they were older, effectively extending their reproductive life span.

On the other hand, introducing a copy of the Chek1 gene into the mice also extended their reproductive life span, but by enabling production of more eggs after birth, which took longer to deplete. These different mechanisms really highlight the complexity in the processes that go into the ovarian reserve, said Rong Li, cell biologist at Johns Hopkins University and professor of the National University of Singapore who studies cellular processes of development.

In the future, researchers hope these findings could lead to therapeutics to extend fertility in women, though it may not be a straightforward process, Murray said. While early menopause was associated with increased risk of type 2 diabetes and worse bone health, it was also associated with decreased risk of breast and ovarian cancer. To avoid detrimental effects of delaying menopause, researchers suggest that therapeutics could be used in the short-term like targeting certain genes to enhance egg production during IVF cycles, for example.

Targeting DNA-repair genes with treatments could also have unintended consequences. Li suggests that other genes may be better targets. [DNA-damage response genes] are a bit scary to manipulate because [by inhibiting them] you could get cancer, said Li, who was not involved with the study but has collaborated with Perry. Other pathways might be better and safer targets for intervention.

More simply, the findings could also be used to provide women with more information about the approximate age when they would get menopause. Predictions about menopause age could inform women of their risk of developing conditions like breast cancer and help their decisions about when to have children, which could help them avoid unnecessary procedures, like infertility treatments.

But because most of the study was done on women of European ancestry, the findings need to be replicated in different populations, said Corrine Welt, an endocrinologist at the University of Utah who studies the genetics of early menopause and who was not involved in the study. When the study did look at women from East Asian ancestry, it found that many of the genetic signals held up but the size of the effect of these genetic regions on menopause timing was different than those in women with European ancestry.

Murray hopes future studies could improve menopause age prediction by also including non-genetic factors that are known to influence ovarian reserve like smoking. Researchers are hopeful that womens reproductive health is finally getting the attention it deserves, which could open the door for more studies and ultimately better health outcomes.

I think with studies like this, we are making a lot of headway, said Welt. Lets study all the female reproductive problems with genetics, because, unfortunately, its been an underserved aspect of medicine.

See more here:
Study finds genetic signals that might be used to predict early menopause - STAT

Introduction

Pancreatic ductal adenocarcinoma (PDAC) ranks among the top leading causes of cancer deaths in the Western world and, in contrast to other tumor entities of the gastrointestinal tract like colorectal cancer, its incidence is rising.1,2 The dismal prognosis of this cancer type is caused by late diagnosis mostly in advanced stages with no chance for curative resection, a very high relapse rate and resistance to most of the tested therapies and targeted drugs.35 Current cancer statistics show a five year survival rate of only 5-10 % with no meaningful improvements during the last 20 years.6

Integrated analysis of the genomic landscape has identified four commonly mutated genes, namely KRAS, TP53, SMAD4, and CDKN2A.79 Given the aforementioned late detection rate, lack of reliable biomarkers and aggressive biology of PDAC, there is a strong need for finding new biomarkers to guide decision-making in the clinical management of patients affected by this type of cancer. One non-invasive and promising tool for early detection, predicting tumor recurrence and monitoring treatment responses as well as resistance is the analysis of circulating tumor DNA (ctDNA). CtDNA is a relatively small and highly variable fraction of circulating cell-free DNA (cfDNA), which is primarily composed of germline DNA that originates from normal cells.10,11 Assessment of ctDNA derived from the primary tumor and metastatic sites, which can be isolated from the peripheral blood provides a real-time picture of the tumor burden and treatment escape mechanism.12,13 Several studies have shown that ctDNA can be used to analyze somatic sequence alterations in various cancers through Next-Generation Sequencing (NGS).1419 In the case of PDAC, a majority of studies report a very high overlap (>50%) of detected mutations between bulk tumor and ctDNA.2026 However, the detection rate for the most frequently mutated gene KRAS largely varies in recently published reports ranging from 21.1% to almost 100%.2036 It is clear that patient selection and related factors such as disease stage as well as the methods, which were used to isolate and analyze the ctDNA are crucial factors for the practical applicability of liquid biopsy in this disease. To date, liquid biopsy for PDAC is not routinely used in the clinic but potential applications range from using it as a prognostic biomarker for survival to monitoring treatment responses and disease recurrence as well as identifying molecular targets for personalized therapy.37 Therefore our aim was to assess the clinical applicability of two commercially available NGS gene panels to detect the most frequent mutations in ctDNA from two consecutive blood samples in patients with non-resectable locally advanced or metastatic PDAC who underwentsystemic treatment.

This is a single-center, prospective, observational study including patients with histologically proven non-resectable PDAC, which was either locally advanced or metastasized and who underwent a systemic treatment at the Medical University of Vienna between 05/2016 and 05/2018. The electronic medical history was queried for patient demographics, performance status, date of diagnosis, date of advanced disease, diagnosis and carbohydrate antigen 199 (CA199) level at baseline, treatment details and survival data. ECOG (Eastern Cooperative Oncology Group) performance status was derived, if not stated explicitly, from the medical history including comorbidities and overall assessment of the treating physician. Recurrent PDAC after resection of curative intent was stated as stage IV disease. The here presented data analysis received prior approval by the ethical committee of the Medical University of Vienna (EK 274/2011) and was performed according to Helsinki criteria of good scientific practice. Written consent of the study participants was obtained after they were informed about the study purpose and prior to study commencement.

Peripheral blood from patients was collected in cell-free DNA collection tubes (Roche) at day one of the first administration of the systemic chemotherapy regimen as well as 46 weeks after the first blood sample. Blood samples were proceeded within 12 hours of collection via a 2-step centrifugation protocol. First, plasma was separated from the other blood components by centrifugation at 2000 x g for 20 minutes. After transferring the upper plasma layer to a new conical tube, it was respun at 3200 x g for 30 minutes to remove cell debris. Subsequently the resulting plasma supernatant was stored at 20 C in 10 mL cryotubes (VWR) until DNA isolation. Circulating DNA isolation from 510 mL plasma was performed on the Chemagic 360 Instrument (Perkin Elmer) with the isolation kit CMG-1111 (chemagic cfDNA 10k Kit special H12) according to manufacturers instruction. Cell-free DNA was eluted in ~40 L elution buffer. DNA quantification was performed with Qubit dsDNA HS Assay Kit (Invitrogen) according to the instructions provided by the manufacturer and purity was determined by Agilent 2200 TapeStation System. Cell-free DNA was stored at 20 C until further analysis.

Genomic DNA was isolated from formalin fixed, paraffin embedded (FFPE) tissue sections using GeneRead DNA FFPE Kit (Qiagen) according to the user manual. DNA quantification was performed with Qubit dsDNA HS Assay Kit (Invitrogen) according to the instructions provided by the manufacturer and purity was determined by Agilent 2200 TapeStation System. Genomic DNA was stored at 20 C until further analysis.

Library preparation was conducted using the Illumina TruSight Tumor 15 covering 15 genes, which are frequently mutated in solid tumors. Subsequent sequencing of pooled libraries was performed in several runs on the MiniSeq Illumina platform using MiniSeq High Output Reagent Kit (300-cycles). Data analysis was conducted using on-instrument Local Run Manager (LRM) Software with TruSight Tumor 15 analysis module. Passed-filter reads were aligned to human reference genome UCSC hg19 using banded Smith Waterman algorithm. Variants were called using Somatic Variant Caller developed by Illumina. All vcf-datasets were annotated using the Illumina VariantStudio 3.0 Software. Across all samples, several hotspot codons were manually evaluated using the Integrative Genomics Viewer (IGV) for potential low-abundance variants (0.1> VAF <2.0%). Annotated plasma variants had to have allele frequencies above a background threshold of the mean of our control samples (three different non-PDAC cfDNA samples).

Library preparation was conducted using AmpliSeq Library PLUS with AmpliSeq Cancer HotSpot Panel v2 for Illumina. This panel is designed to amplify 207 amplicons covering hotspot regions of 50 genes with known association to cancer. Final libraries were sequenced together using MiniSeq High Output Reagent Kit (300-cycles). Data analysis was conducted using DNA Amplicon workflow via Basespace Sequence Hub. The NGS data alignment was performed with Burrows-Wheeler Aligner (BWA) and subsequently Somatic Variant Caller was used. Variant annotation was performed with Illumina VariantStudio 3.0 Software. Across all samples, several hotspot codons were manually evaluated using the Integrative Genomics Viewer (IGV) for potential low-abundance variants (0.1> VAF <2.0%). Annotated plasma variants had to have allele frequencies above a background threshold of the mean of our control samples (HD701 and HD729 Reference Standards (Horizon)).

Descriptive statistics were calculated as mean, median or percentages as appropriate. Correlation between variant allele frequencies (VAF) between the two panels was calculated with Spearman correlation coefficient. The threshold for statistical significance was set at a p-value of less than 0.05.

A total of 21 patients with histologically proven PDAC were included in this study. Table 1 lists patient and tumor characteristics. There were 12 female (57.1%) and nine male (42.9%) patients. The median age at time of diagnosis of advanced disease was 64.3 years (interquartile range (IQR) 57.968.9 years). Three patients (14.3%) presented with locally advanced (unresectable) disease and 18 patients (85.7%) had metastasis at time of study inclusion. There were eight patients (38.1%) with a prior surgical resection. The median CA 199 levels were 481.5 kU/l (IQR 59.43355.0 kU/l). Levels of CA 199 were within the normal range in three patients (14.3%) and above in 18 patients (85.7%). The primary site of metastatic disease was liver (n = 11; 52.4%) followed by peritoneum (n = 5; 23.8%) and lung (n = 4; 19%). There were three patients (14.3%) with locally advanced disease, while 14 patients (66.7%) had one organ affected by metastatic spread and four patients (19%) had two or over two metastatic sites. The ECOG performance status was zero in 17 patients (81%) and one in four patients (19%).

Table 1 Characteristics of Patients and Tumors

In general, the amount of cfDNA, which can be obtained from plasma is relatively small compared to genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. Moreover, the fraction of cfDNA that originates from tumor cells (ctDNA) is extremely low. First, we analyzed quantity and quality of our cfDNA, which has been isolated using a magnetic bead-based protocol applicable for higher plasma volumes. All samples were isolated successfully and compared to other studies we revealed a considerably high mean cfDNA value of 1.9 ng/L (range 0.494.76 ng/L) in a volume of ~40 L.33,38,39 One sample yielded 53 ng/L cfDNA, which is substantially higher than the cfDNA amount of other samples and therefore not included into the mean-calculation. Due to the high concentration of DNA, we wanted to exclude contamination with high-molecular weight genomic DNA (gDNA) wherefore we performed fragment size analysis with the TapeStation System. CfDNA is highly fragmented and shows a size distribution of ~ 130 bp-180 bp. Generally, fragments higher than 1000 bp are considered as gDNA. The average cfDNA peak of our samples was around 180 bp and shows that there is little to no genomic DNA contamination (see quality control of representative PDAC samples in Supplementary Figure S1). Even the quality of the cfDNA sample with 53 ng/L was sufficient for NGS (Supplementary Figure S2). In summary, we conclude that all our samples were suitable for downstream applications such as NGS without any adaptation, which usually are necessary in cases of low cfDNA yields.

In a next step, we analyzed a total of 42 samples from 21 PDAC patients using a small gene panel containing 15 genes with a high coverage and high sensitivity. Paired-end sequencing resulted in average 3.84 Mio passed filter reads per sample and mean amplicon coverage of 23.086. The ctDNA variant detection limit depends on the background signal of our control samples. The control samples revealed allelic frequencies of 00.21%.

Sixteen out of 21 sequenced patients (76.2%) exhibited at least one variant (see Figure 1A). The number of gene mutations per patient ranged from 1-3 in at least one time point. The identified variants revealed allelic frequencies of 0.122% and were distributed over the following six cancer-related genes: KRAS (n = 14; 66.6%), TP53 (n = 7; 33.3%), PIK3CA (n = 2; 9.5%), EGFR (n = 1; 4.8%), MET (n = 1; 4.8%), PDGFRA (n = 1; 4.8%) (see Figure 1B). All detected variants with known or likely pathogenic effect are listed in detail in Supplementary Table S1. In all 16 patients at least one mutation was detected at baseline level. In eight of 16 patients (50%) all baseline variants were still found in the follow-up sample at varying percentages. In two patients (12.5%) (#3 and #15) one baseline mutation was also present in the follow-up sample at varying frequencies while a new mutation was identified in the subsequent sample and appeared during therapy. In patient #7 two baseline variants were also present with very low allele frequency in the consecutive sample while a TP53 variant disappeared. In the remaining five patients (31.3%) the baseline mutation was not detectable in the second sample. In summary, our 15-gene panel was sufficient to identify at least one tumor-associated mutation in 76.2% of our cases, which was suitable for follow-up monitoring.

Figure 1 Comparison between GP15 and GP50. Ratio of patients with at least one detectable mutation versus no detectable mutation according to the two panels (A). Absolute numbers of mutations detected with the two panels (B). Venn diagrams showing the number of patients with shared or exclusive mutations detected by the two panels (C). Correlation between variant allele frequency (VAF) between the two panels, r = Pearson r, P = p-value (D).

Since KRAS, TP53, SMAD4, and CDKN2A are known driver genes for PDAC and GP15 does not cover the latter two, all 42 samples were concomitantly analyzed with a larger panel containing 50 genes, which automatically leads to lower coverage and thus lower sensitivity. Paired-end sequencing resulted in average 1.08 Mio passed filter reads per sample and mean amplicon coverage of 4370. The detection limit of cfDNA variants depends on the background signal of our control samples, which revealed allelic frequencies of 00.149%. Sixteen out of 21 sequenced patients (76.2%) exhibited at least one variant (see Figure 1A). The number of gene mutations per patient ranged from 1-4 in at least one time point. The identified variants revealed allelic frequencies of 0.1723% and were distributed over the following five cancer-related genes: KRAS (n = 10; 47.6%), TP53 (n = 9; 42.8%), SMAD4 (n = 5; 23.8%), CDKN2A (n = 2; 9.5%), PIK3CA (n = 1; 4.8%) (see Figure 1B). All detected variants with known or likely pathogenic effect are listed in detail in Supplementary Table S2. In patient #5 a mutation was only detectable in the consecutive sample, but not at baseline. In six patients the baseline variants were still found in the follow-up sample at varying percentages. In patient #4 one baseline mutation was also present in the consecutive sample while an additional mutation disappeared during therapy. In patient #2 the baseline mutations were not detectable during therapy, but a new variant emerged in the follow-up sample reflecting different subclones. In the remaining seven patients the detected baseline mutation disappeared under therapy. In summary, with this 50-gene panel we were able to detect at least one tumor-associated mutation in 76.2% of our cases, even if the variant-frequency of some mutations is very low.

As stated above, KRAS and TP53 are the two most commonly mutated genes in PDAC. The overlap for these two genes in our samples analyzed with GP15 and GP50 is shown in Figure 1C. Moreover, a strong correlation of the variant allele frequency (VAF) for KRAS (Pearson r (r) = 0.9868, p =< 0.0001) and TP53 (r = 0.9854, p = 0.0001) between the two sequencing panels for all analyzed samples was observed (see Figure 1D).

When comparing GP15 results with GP50, nine out of 21 patients (43.2%) revealed the same results regarding the GP15 genes. Five patients showed additional KRAS-mutations with GP15, which were not detectable with GP50 because of the low variant-frequency. Patients #3 and #5 had, among others, PIK3CA and MET mutations, respectively. These gene regions are not covered by GP50 and therefore were not detected. In two patients (#17 and #19) a low-frequency TP53 mutation was detected with GP50 (Figure 1C), which was found by GP15 as well, but hadto be excluded because the allele frequency was not above the background threshold.

As aforementioned, SMAD4 and CDKN2A are frequently mutated genes in PDAC, but both genes are not covered by GP15. In this sense, in five GP15-positive cases additional variants in SMAD4 and CDKN2A were detected with GP50. Moreover, in one GP15-negative patient (#6) we could identify SMAD4 and CDKN2A mutations, even though they are low-frequency variants.

Ultimately, we have summarized the GP15 results with the two genes SMAD4 and CDKN2A, which were analyzed with GP50. Overall, 24 different variants with known or likely pathogenic effects were detected. The most commonly altered variants were KRAS p.G12D (n = 5), KRAS p.G12V (n = 3), KRAS p.G12R (n = 3) and the low-frequency variant CDKN2A p.Y129C (n = 2). All detected variants and the individual response to therapy are listed in detail in Table 2. In summary, four out of 21 (19.04%) cases revealed no pathogenic variants. It has been shown in previous studies that a therapy response is associated with a decreasing or unchanged mutant allele frequency, whereas an increase of ctDNA is associated with refractory disease.38,40,41 As a result, in seven of 21 (33.33%) PDAC patients the observed ctDNA dynamics suggests a correlation between ctDNA levels and response/non-response to cancer treatment. In ten of 21 (47.62%) patients a discordance of genetic and clinical data was observed (Table 2).

Table 2 Mutational Profile of 21 PDAC Patients (GP15 Results Combined with GP50 SMAD4 and CDKN2A Results). Paired-End Sequencing Resulted in a Mean Amplicon Coverage of 23.086 (GP15) and 4370 (GP50), respectively.

Depending on the availability, FFPE tissue samples of the primary tumor (n = 8) or liver metastasis (n = 3) were retrieved. To compare the mutations of the primary (FFPE) and recurrent tumor (which is represented by the ctDNA) the GP15 was used. In tissue DNA, alterations in KRAS were observed in all (n = 11) and in TP53 in 81% (n =9) of the available samples. In five (45.45%) patients blood-tissue mutational profiles were fully concordant (Table 3). KRAS and TP53 mutations were detectable in the tumor tissue of three (27.27%) patients, while ctDNA analysis only revealed the KRAS mutation in the respective sample (partially concordant mutational profiles). The remaining three (27.27%) patients only had detectable TP53 and/or KRAS mutations in the primary tumor or liver metastases but not in the corresponding ctDNA analysis with the GP15. Overall, genomic concordance rate between tissue DNA and ctDNA analyses was 65.22%, which means that 15/23 mutations that were present in the primary tumor/metastatic site could also be detected in ctDNA. More precisely, concordance rate was 72.72% for KRAS and 44.44% for TP53.

Table 3 Comparison of Mutations of cfDNA (Baseline) and Primary Tumor Sample/Metastatic Site of Eleven PDAC Patients

Liquid biopsy is increasingly recognized as a versatile tool for the detection of disease relapse and treatment monitoring of cancer patients.42,43 However, the plethora of potential methods, ranging from PCR-based techniques to NGS-based systems, complicates the comparison between different studies and ultimately limits the conclusions, which could be drawn on their clinical utility. Due to declining costs, the wide availability and the possibility to simultaneously detect multiple different mutations, NGS-based methods have also become very popular when analyzing low input samples like ctDNA from blood plasma of cancer patients. Given that a substantial proportion of patients, even if they present with metastatic disease, have unexpectedly low amounts of ctDNA,44 it is important to consider that the coverage of the used sequencing panel is mostly determined by the number of analyzed genes. The aim of this study was to assess the clinical applicability of two commercially available NGS gene panels (15 versus 50 genes), to detect the most frequent mutations in ctDNA from two consecutive blood samples in patients with advanced PDAC, which undergo systemic treatment.

Generally, the amount of total cfDNA, which can be isolated from plasma is quite small. Most studies give remarkably little detail about the quantity of cfDNA, which they have gained with their chosen DNA extraction methods. Some few studies reported about cfDNA levels in PDAC patients, which are much lower than our yield.33,38,39 By using a bead-based isolation approach applicable for higher plasma volumes, we were able to obtain relatively high mean cfDNA values (1.9 ng/L in a volume of ~40 L) with minimal genomic DNA contamination. These samples were suitable for NGS without any adaptation. The cfDNA sample collected at the second time point of patient #10 revealed a concentration of 53 ng/L, much higher than our mean value. Such a high value suggests the assumption that genomic DNA contamination is present; even so the quality control displayed a characteristic profile of cfDNA (Supplementary Figure 2). Therefore, this sample was used for further analysis without any concerns. A non-malignant pathological process leading to the release of high amounts of cfDNA into the blood stream4547 cannot be the only explanation since KRAS p.G12V variant allele frequency was almost unchanged in both samples (Table 2) despite of 20x cfDNA concentration differences (2.51 ng/L versus 53.0 ng/L).

To the best of our knowledge, we present here for the first time results of this promising isolation approach. Some downstream applications require high levels of cfDNA, therefore our results could be of interest for the medical and biobanking communities.

With our 15-gene panel at least one tumor-associated mutation in 76.16% of the patients in our cohort could be identified. With our 50-gene panel we were able to detect in 76.16% of the cases a mutation as well; even though the mutation-positive cases are slightly different. Differences are mainly caused by the number of assessed genes, amplicon coverages and amplicon positions. Variant allele frequency of some mutations detected with the 50-gene panel is very low. Although we have used controls to determine the background threshold, these results are still not reliable enough for routine clinical practice, as with the TP53 low-frequency variants in patients #17 and #19. One possible option to overcome this issue is to combine NGS results with droplet digital PCR just for specific low-frequency mutations.31 Since droplet digital PCR is a more sensitive method,48,49 it would help to validate true positive low-level mutations detected by NGS.

Despite the same detection rate of 76.16% for at least one mutation, the 15-gene panel seems to be more informative (five additional KRAS mutations were detected), sensitive and reliable based on our results in respect of routine clinical practice.

During tumorigenesis KRAS mutations are among the first to occur and consequently they are seen as founder mutations.32335052 Correspondingly, KRAS is the most frequently mutated gene in patients with PDAC. In accordance with these studies, we also predominantly detected mutations in KRAS, more precisely in codon 12.31 In general, therapy response is associated with a decreasing or unchanged mutant allele frequency, whereas an increase of ctDNA is associated with refractory disease.38,40,41 With both our panels we were able to observe changes of the ctDNA allele frequencies under therapy. In 33.33% (7/21) of our cases a correlation between mutational frequency and therapy response assessed by CT-scans can be assumed. For example in patient #14 the mutational frequencies of both detected mutations dropped and correspondingly the follow-up CT-scan showed that the tumor lesions were not progressing. Furthermore, it can be hypothesized that both mutations originate from the same tumor clone because of the similar allele frequency (Table 2). In contrast, in 47.62% (10/21) of our cases a discordance of genetic and clinical data was observed. Patient #4 revealed a KRAS and TP53 mutation and the allele frequency of both decreased during therapy, which would indicate a therapy response. Contrary to this, disease reassessment by CT-scan revealed a disease progression. Based on such findings we propose that it is important to be cautious with the interpretation of mutation frequencies in respect to clinical response. Furthermore, in patients #12 and #17 baseline mutations were not detectable during therapy, although disease reassessment showed a stable disease. Regarding the radiological response evaluation, it should be considered that standard imaging methods cannot always reliably distinguish between vital tumor tissue and fibrotic masses, which could complicate the assessment of treatment responses.

In eleven of 21 patients (52.38%) primary tissue or metastatic sites were analyzed for comparison. In 5/11 patients sequencing analysis revealed a complete blood-tissue concordance of the mutational landscape and in 3/11 patients there was a partial concordance. In the latter case (#8, #11 and #21), KRAS mutations are presented in both analyses, whereas TP53 mutations were not detectable in ctDNA. One possible explanation for the absence of TP53 mutations could be a different clonal composition of the tumor in further treatment lines compared to the primary tumor. Treatment could have eradicated most of these clones during first line treatment.53 In patients #18 and #20 KRAS and TP53 mutations were detected only in the tissue of the primary tumor or metastasis but missing in ctDNA analyses. A reason for the discrepancy in the mutational profile between tissue and ctDNA might be low ctDNA levels in these samples, a limitation, which has been described in patients who are under treatment.39,53,54 In summary, the genomic concordance rate between tissue and ctDNA in our cohort was 65.22% for all mutations and in particular 72.72% for KRAS, which is higher than the rates reported by a previous study from Patel et al.25 These results emphasize the potential of ctDNA as a biomarker in PDAC and underline the promising cfDNA-isolation technique.

Limitations of this study are the relatively small number of included patients and that blood samples were only collected early in the treatment course, which would miss potential outgrowing tumor clones that arise shortly before therapy response evaluation. We decided to collect blood samples early in the treatment course because we speculated to be able to anticipate the treatment response before radiological reassessment would be performed. Our results demonstrate that by following these early ctDNA dynamics we were successful in predicting the clinical outcome in about half of all patients with a detectable mutation at baseline. In the other half of the patients treatment responses were not predictable. The selection of the NGS sequencing panels was based on the covered genes, however at the time of study initiation no PDAC-specific product suitable for ctDNA was available. We would highly encourage the development of a commercially available NGS sequencing panel optimized for ctDNA analysis in PDAC, which focuses only on a limited number of genes that are typically mutated in this disease, like KRAS, TP53, CDKN2A, SMAD4, and KDM6A. With this gene panel it would be possible to simultaneously assess multiple genes to maximize the rate of patients with at least one mutation, which can be monitored during therapy while maintaining a sufficiently high coverage essential for detecting low-abundance ctDNA.

This study demonstrates the feasibility of using an NGS-based analyzing method for ctDNA in PDAC patients undergoing a palliative chemotherapy. Ourresults underscore the importance of precise DNA isolation to yield high quality samples for further ctDNA analysis and the selection of a gene panel with a high coverage. Further validation of our findings, with a specifically for this purpose developed NGS-based gene panel, in a larger patient cohort is warranted.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

We want to thank Robert Brettner for the processing of plasma samples and Sarah Szaffich for her great technical support. Thanks to Dr. Judith Stift for the estimation of the tumor-harboring areas on HE stained FFPE tissue slices. All sequencing was performed in cooperation with the Core Facility Genomics of the Medical University Vienna. This work was supported by the Fonds der Stadt Wien fr innovative interdisziplinre Krebsforschung.

This research received no external funding.

GWP: Personal financial interests: Merck Serono, Roche, Amgen, Sanofi, Lilly, Servier, Taiho, Bayer, Halozyme, BMS, Celgene, Pierre Fabre, Shire, Institutional financial interests Clinical trials: Celgene, Array, Servier, Bayer, BostonBiomedical, Merck, BMS. All other authors declare no conflict of interest.

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Bead-based Isolation of Circulating Tumor DNA - CMAR | CMAR - Dove Medical Press

Some sections of our DNA are genes, which are instructions for building proteins, while other sections called enhancers regulate which genes are switched on or off, when, and in which tissue. New research from the University of Copenhagen and the Karolinska Institutet provides evidence of a functional link between epigenetic rewiring of enhancers to control their activity after exercise training and the modulation of disease risk in humans.

Exercise training rewires the enhancers in regions of our DNA that are known to be associated with the risk to develop disease. Image credit: Sasin Tipchai.

Regular physical activity decreases the risk of multiple common disorders such as cardiovascular disease, type 2 diabetes, cancer, and neurological conditions, along with the overall risk of mortality, said Professor Romain Barrs from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen and colleagues.

The beneficial effects of exercise training on human health are partially driven by adaptations of the skeletal muscle tissue.

Exercise-induced adaptations include coordinated changes in the expression of genes controlling substrate usage and metabolic efficiency in skeletal muscle.

In addition to the adaptations that occur within skeletal muscle cells, exercise exerts systemic effects on whole-body homeostasis by triggering the release of soluble factors from the muscle that signal to distal tissues, such as brain, liver, and adipose tissue.

The mechanisms by which training-induced adaptations of skeletal muscle orchestrate positive effects at the whole-body level are poorly understood.

We hypothesized that endurance exercise training remodels the activity of gene enhancers in skeletal muscle and that this remodeling contributes to the beneficial effects of exercise on human health.

For the study, the researchers recruited eight healthy Caucasian men (mean age 23 years) and put them through a six-week endurance exercise program.

They collected a biopsy of their thigh muscle before and after the exercise intervention and examined if changes in the epigenetic signature of their DNA occurred after training.

They discovered that after completing the endurance training program, the structure of many enhancers in the skeletal muscle of the young men had been altered.

By connecting the enhancers to genetic databases, the scientists found that many of the regulated enhancers have already been identified as hotspots of genetic variation between individuals.

Our findings provide a mechanism for the known beneficial effects of exercise, Professor Barrs said.

By connecting each enhancer with a gene, we further provide a list of direct targets that could mediate this effect.

The authors speculate that the beneficial effects of exercise on organs distant from muscle, like the brain, may largely be mediated by regulating the secretion of muscle factors.

In particular, they found that exercise remodels enhancer activity in skeletal muscle that are linked to cognitive abilities, which opens for the identification of exercise training-induced secreted muscle factors targeting the brain.

Our data provides evidence of a functional link between epigenetic rewiring of enhancers to control their activity after exercise training and the modulation of disease risk in humans, said Dr. Kristine Williams, also from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen.

The findings are published in the journal Molecular Metabolism.

_____

Kristine Williams et al. Epigenetic rewiring of skeletal muscle enhancers after exercise training supports a role in the whole-body function and human health. Molecular Metabolism, published online July 10, 2021; doi: 10.1016/j.molmet.2021.101290

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Study: Physical Exercise Improves Health of Brain and Other Organs through Epigenetic Changes | Medicine, Physiology - Sci-News.com

Dr. Tadataka Tachi Yamada/Photo Courtesy of Getty Images.

In the midst of the biggest global health crisis in a generation, the world has lost one of its premier global public health advocates. Dr. Tadataka Tachi Yamada, a former GlaxoSmithKline and Takeda Pharmaceutical executive, early gene therapy backer, and philanthropist, passed away on Wednesday of natural causes at the age of 76.

Born in Japan,Yamada eventually moved to the United States and trained as a gastroenterologist. He began his impactful career in academia where he rose to Chief of the Division of Gastroenterology and chair of the Department of Internal Medicine at the University of Michigan. He then made the pivot to the Life Sciences, becoming the Chairman of Research and Development for GSK.

Yamada made the decision to move into industry to make a more direct impact on patients.

Youre working in the laboratory; youre doing research thats pretty basic. And you feel like this work is going to actually have an impact on patients somewhere down the line, but youre never sure, and youre pretty distant from any direct effect on patients, he said in a 2012 interview with the Journal of Clinical Investigation (JCI). When I went, I realized that these people were really serious and had a very difficult task. Making medicines is maybe the hardest task in biomedical science.

Yamada might be best known and remembered for his philanthropic efforts in the development of vaccines for malaria and meningitis. In 2009, he left GSK to join the Bill & Melinda Gates Foundation as executive director of the Global Health program.

In 2013, Yamada heard the industry calling again, joining Takeda as EVP and Chief Medical and Scientific Officer where he shepherded the launch of Takeda Vaccines, which is in the late stages of developing just the second vaccine for the mosquito-borne virus, dengue fever.

In recent years, Yamada founded or co-founded a series of biopharma companies committed to developing vaccines and therapeutics for the diseases closest to his heart. These include Icosavax, Inc., which is focused on developing safe and effective vaccines against infectious diseases, and Passage Bio, a clinical-stage genetic medicines company in the CNS space which he co-founded in 2017 with gene therapy pioneer, Dr. James Wilson.

We are deeply saddened by the sudden passing of Tachi, a visionary leader in our field and co-founder of Passage Bio, said Passage president and CEO, Bruce Goldsmith, Ph.D. We are forever grateful for the vision, scientific experience, and strategic influence that he shared to establish our company. He has left a lasting legacy with his generous contribution to our industry, and specifically to Passage Bio and the patients we serve. We will continue to honor and build upon Tachis legacy.

Prior to his death, Yamada was a venture partner with Frazier Healthcare and served as chair of the board of directors at the Clinton Health Access Initiative.

Dr. Tachi Yamada was an extraordinary scientist and leader who used his brilliant mind and kind, good heart to improve the lives of millions of people, former president Bill Clinton said in a statement. Tachi brought a world of experience, knowledge, and good judgement to CHAI. He inspired us all to help more people and save more lives.

Tributes also poured in from Alnylam Pharmaceuticals CEO, John Maraganore and Dr. Peter Singer, special advisor toDirector General Tedros Adhanom Ghebreyesus at the World Health Organization (WHO).

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The World Takes Another Hit with Loss of Global Health Giant Dr. Tachi Yamada - BioSpace

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the pivotal Phase III POLARIX trial investigating Polivy (polatuzumab vedotin) in combination with Rituxan (rituximab) plus cyclophosphamide, doxorubicin and prednisone (R-CHP) versus Rituxan plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) met its primary endpoint by demonstrating significantly improved and clinically meaningful progression-free survival in people with previously untreated diffuse large B-cell lymphoma (DLBCL). Safety outcomes were consistent with those seen in previous trials.

Since 40% of people with DLBCL relapse after initial therapy, achieving meaningful treatment effects in the front-line setting has the potential to be transformative, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. This Polivy regimen is the first in two decades to improve progression-free survival in DLBCL compared to the standard of care, and we look forward to sharing these results with health authorities to bring this important potential new treatment option to patients as soon as possible.

Todays POLARIX results will be presented at an upcoming medical meeting and submitted to health authorities as part of Genentechs commitment to transforming the treatment of DLBCL by providing options tailored to patient and healthcare professional needs. Genentech would like to thank all investigators, academic partners and people with DLBCL who participated in the study.

Currently, Polivy is used as an off-the-shelf, fixed-duration treatment option in the relapsed or refractory (R/R) DLBCL setting, and is approved in combination with bendamustine and Rituxan for the treatment of R/R DLBCL in more than 60 countries worldwide, including in the EU and in the U.S. Genentech continues to explore areas of unmet need where Polivy has the potential to deliver benefit, with ongoing studies investigating combinations of Polivy with the CD20xCD3 T cell-engaging bispecific antibodies mosunetuzumab and glofitamab, with Venclexta (venetoclax), which is being developed by AbbVie and Genentech, and with Rituxan in combination with gemcitabine and oxaliplatin in the Phase III POLARGO study.

About the POLARIX study

POLARIX [NCT03274492] is an international Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy, safety and pharmacokinetics of Polivy (polatuzumab vedotin) plus Rituxan (rituximab), cyclophosphamide, doxorubicin and prednisone (R-CHP) versus Rituxan, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in people with previously untreated diffuse large B-cell lymphoma (DLBCL). Eight-hundred and seventy-nine patients were randomized 1:1 to receive either Polivy plus R-CHP plus a vincristine placebo for six cycles, followed by Rituxan for two cycles; or R-CHOP plus a Polivy placebo for six cycles, followed by two cycles of Rituxan. The primary outcome measure is progression-free survival as assessed by the investigator using the Lugano Response Criteria for malignant lymphoma. POLARIX is being conducted in collaboration with The Lymphoma Study Association (LYSA) and The Lymphoma Academic Research Organisation (LYSARC).

About Polivy (polatuzumab vedotin-piiq)

Polivy is a first-in-class anti-CD79b antibody-drug conjugate (ADC). The CD79b protein is expressed specifically in the majority of B cells, an immune cell impacted in some types of non-Hodgkins lymphoma (NHL), making it a promising target for the development of new therapies. Polivy binds to CD79b and destroys these B cells through the delivery of an anti-cancer agent, which is thought to minimize the effects on normal cells. Polivy is being developed by Genentech using Seagen ADC technology and is currently being investigated for the treatment of several types of NHL.

About DLBCL

DLBCL is the most common form of non-Hodgkins lymphoma (NHL), accounting for about one in three cases of NHL. DLBCL is an aggressive (fast-growing) type of NHL. While it is generally responsive to treatment in the frontline, as many as 40% of patients will relapse or have refractory disease, at which time salvage therapy options are limited and survival is short. Approximately 150,000 people worldwide are estimated to be diagnosed with DLBCL each year.

Polivy U.S. Indication

Polivy is a prescription medicine used with other medicines, bendamustine and a rituximab product, to treat diffuse large B-cell lymphoma in adults who have progressed after at least two prior therapies.

The accelerated approval of Polivy is based on a type of response rate. There are ongoing studies to confirm the clinical benefit of Polivy.

Important Safety Information

Possible serious side effects

Everyone reacts differently to Polivy therapy, so its important to know what the side effects are. Some people who have been treated with Polivy have experienced serious to fatal side effects. A patients doctor may stop or adjust a patients treatment if any serious side effects occur. Patients must contact their healthcare team if there are any signs of these side effects.

Side effects seen most often

The most common side effects during treatment were

Polivy may not be for everyone. A patient should talk to their doctor if they are

These may not be all the side effects. Patients should talk to their healthcare provider for more information about the benefits and risks of Polivy treatment.

Report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Please visit http://www.Polivy.com for the full Prescribing Information for additional Important Safety Information.

About Genentech in Hematology

For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, were investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit http://www.gene.com/hematology.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

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Phase III Study Shows Genentech's Polivy Plus R-CHP Is the First Regimen in 20 Years to Significantly Improve Outcomes in Previously Untreated...

Aug. 3, 2021 05:00 UTC

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has accepted the companys supplemental Biologics License Application (sBLA) and granted Priority Review for Tecentriq (atezolizumab) as adjuvant treatment following surgery and platinum-based chemotherapy for people with non-small cell lung cancer (NSCLC) whose tumors express PD-L11%, as determined by an FDA-approved test. The FDA is reviewing the application under the Real-Time Oncology Review pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible. The FDA is expected to make a decision on approval by December 1, 2021.

New treatment options are urgently needed in early-stage non-small cell lung cancer to help the nearly 50% of people who currently experience a recurrence following surgery, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. Tecentriq is the first cancer immunotherapy to show a clinically meaningful benefit in the adjuvant lung cancer setting, and were working closely with the FDA to bring this significant advancement to patients as quickly as possible.

This application is based on disease-free survival (DFS) results from an interim analysis of the Phase III IMpower010 study, the first and only Phase III study of a cancer immunotherapy to demonstrate positive results in the adjuvant lung cancer setting. The study showed that treatment with Tecentriq following surgery and platinum-based chemotherapy reduced the risk of disease recurrence or death (DFS) by 34% (hazard ratio [HR]=0.66, 95% CI: 0.50-0.88) in people with Stage II-IIIA NSCLC whose tumors express PD-L11%, compared with best supportive care (BSC). In this population, median DFS was not yet reached for Tecentriq compared with 35.3 months for BSC. Follow-up on the IMpower010 trial will continue with planned analyses of DFS in the overall intent-to-treat (ITT) population, including Stage IB patients, which at the time of analysis did not cross the threshold, and overall survival (OS) data, which were immature at the time of interim analysis. Safety data for Tecentriq were consistent with its known safety profile and no new safety signals were identified. Results from the IMpower010 trial were presented at the 2021 ASCO Annual Meeting.

About the IMpower010 study

IMpower010 is a Phase III, global, multicenter, open-label, randomized study evaluating the efficacy and safety of Tecentriq compared with BSC, in participants with Stage IB-IIIA NSCLC (UICC 7th edition), following surgical resection and up to 4 cycles of adjuvant cisplatin-based chemotherapy. The study randomized 1,005 people with a ratio of 1:1 to receive either Tecentriq (up to 16 cycles) or BSC. The primary endpoint is investigator-determined DFS in the PD-L1-positive Stage II-IIIA, all randomized Stage II-IIIA and ITT Stage IB-IIIA populations. Key secondary endpoints include OS in the overall study population, ITT Stage IB-IIIA NSCLC.

About lung cancer

According to the American Cancer Society, it is estimated that more than 235,000 Americans will be diagnosed with lung cancer in 2021, and NSCLC accounts for 80-85% of all lung cancers. Today, about half of all people with early lung cancer still experience a cancer recurrence following surgery, but treating lung cancer early, before it has spread, may help prevent the disease from returning and provide people with the best opportunity for a cure.

About Tecentriq (atezolizumab)

Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1. Tecentriq is designed to bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the re-activation of T cells. Tecentriq may also affect normal cells.

Tecentriq U.S. Indications

Tecentriq is a prescription medicine used to treat adults with:

A type of lung cancer called non-small cell lung cancer (NSCLC).

A type of lung cancer called small cell lung cancer (SCLC).

It is not known if Tecentriq is safe and effective in children.

Important Safety Information

What is the most important information about Tecentriq?

Tecentriq can cause the immune system to attack normal organs and tissues in any area of the body and can affect the way they work. These problems can sometimes become severe or life threatening and can lead to death. Patients can have more than one of these problems at the same time. These problems may happen anytime during their treatment or even after their treatment has ended.

Patients should call or see their healthcare provider right away if they develop any new or worse signs or symptoms, including:

Lung problems

Intestinal problems

Liver problems

Hormone gland problems

Kidney problems

Skin problems

Problems can also happen in other organs.

These are not all of the signs and symptoms of immune system problems that can happen with Tecentriq. Patients should call or see their healthcare provider right away for any new or worse signs or symptoms, including:

Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:

Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if patients undergo transplantation either before or after being treated with Tecentriq. A healthcare provider will monitor for these complications.

Getting medical treatment right away may help keep these problems from becoming more serious. A healthcare provider will check patients for these problems during their treatment with Tecentriq. A healthcare provider may treat patients with corticosteroid or hormone replacement medicines. A healthcare provider may also need to delay or completely stop treatment with Tecentriq if patients have severe side effects.

Before receiving Tecentriq, patients should tell their healthcare provider about all of their medical conditions, including if they:

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of Tecentriq when used alone include:

The most common side effects of Tecentriq when used in lung cancer with other anti-cancer medicines include:

Tecentriq may cause fertility problems in females, which may affect the ability to have children. Patients should talk to their healthcare provider if they have concerns about fertility.

These are not all the possible side effects of Tecentriq. Patients should ask their healthcare provider or pharmacist for more information about the benefits and side effects of Tecentriq.

Report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

Report side effects to Genentech at 1-888-835-2555.

Please see http://www.Tecentriq.com for full Prescribing Information and additional Important Safety Information.

About Genentech in cancer immunotherapy

Genentech has been developing medicines to redefine treatment in oncology for more than 35 years, and today, realizing the full potential of cancer immunotherapy is a major area of focus. With more than 20 immunotherapy molecules in development, Genentech is investigating the potential benefits of immunotherapy alone, and in combination with various chemotherapies, targeted therapies and other immunotherapies with the goal of providing each person with a treatment tailored to harness their own unique immune system.

In addition to Genentechs approved PD-L1 checkpoint inhibitor, the companys broad cancer immunotherapy pipeline includes other checkpoint inhibitors, individualized neoantigen therapies and T cell bispecific antibodies. For more information visit http://www.gene.com/cancer-immunotherapy.

About Genentech in lung cancer

Lung cancer is a major area of focus and investment for Genentech, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have five approved medicines to treat certain kinds of lung cancer and more than 10 medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210802005854/en/

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FDA Grants Priority Review to Genentech's Tecentriq as Adjuvant Treatment for Certain People With Early Non-small Cell Lung Cancer - BioSpace

This study describes the findings from the targeted delivery of gene therapy to midbrain to treat a rare deadly neurodevelopmental disorder in children with a neurogenetic disease, aromatic L-amino acid decarboxylase (AADC) deficiency characterized by deficient synthesis of dopamine and serotonin.

The directed gene therapy in seven children ages 4 to 9 who were infused with the viral vector resulted in dramatic improvement of symptoms, motor function and quality of life. Six children were treated at UCSF Benioff Childrens Hospital in San Francisco and one at Ohio State Wexner Medical Center. This therapeutic modality promises to transform the treatment of AADC deficiency and other similar disorders of the brain in the future, Bankiewicz said.

Researchers believe this same method of gene therapy can be used to treat other genetic disorders as well as common neurodegenerative diseases, such as Parkinsons and Alzheimers disease. Clinical trials are underway to test this procedure in others living with debilitating and incurable neurological conditions.

The directed gene therapy, in these patients, resulted in dramatic improvement of symptoms, motor function and quality of life. This therapeutic modality promises to transform the treatment of AADC deficiency and other similar disorders of the brain in the future.

The findings described in this study are the culmination of decades of work by teams from multiple academic institutions, including University of California San Francisco, Washington University in St. Louis, Medical Neurogenetics Laboratory in Atlanta, St. Louis Childrens Hospital and Nationwide Childrens Hospital in Columbus, Ohio.

This work provides a framework for the treatment of other human nervous system genetic diseases. Its our hope that this will be first of many ultra-rare and other neurologic disorders that will be treated with gene therapy in a similar manner, Bankiewicz said.

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Here is the original post:
Innovative gene therapy 'reprograms' cells to reverse neurological deficiencies - Wexner Medical Center - The Ohio State University

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

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

A Charlotte baby became the first at UNC Medical Center in Chapel Hill, N.C. to receive a breakthrough gene therapy treatment for spinal muscular atrophy (SMA), after his condition was discovered through the Early Check newborn screening pilot study.

It was a pregnancy that went relatively smooth. No red flags. No urgent ultrasounds. But, for this one family of Charlotte, N.C., that sense of apprehension was always lurking.

It was like I was waiting for the other shoe to drop. After all that we went through with our first child, once we had our son, it seemed too easy to feel like everything was normal, said the mom, who wishes to be anonymous.

Their first child was born with health issues that went undetected during the moms pregnancy, and it was a surprise at birth.

So, my pregnancy with my second child, my son, was super simple aside from the fact that I would consider myself slightly traumatized from what happened with my oldest. Other than that, the pregnancy was easy and enjoyable, she said.

Their son was born February 25th, 2021, perfect in every way, at least on the outside. Around this time the parents received an envelope in the mail informing them about Early Check, a pilot study focused on screening newborns for rare health conditions, and how parents could sign their babies up prenatally or postnatally.

After speaking with our pediatrician, and realizing how enrolling our son in this study could make a difference, we decided to register, said the mom, whose intuition also played a role in her familys decision. Little did she know her gut decision would allow her child to live a more normal life.

The pilot study is in collaboration between RTI International, North Carolina State Laboratory of Public Health (NCSLPH), and three major universities the University of North Carolina at Chapel Hill, Duke University and Wake Forest University. Among many other rare conditions, Early Check launched screening for spinal muscular atrophy (SMA) in October 2018 throughout the spring of 2021.

With Early Check, we started including SMA because it wasnt a part of the general newborn screening for the state, so it was a pilot to see how it could work and to see if we could identify this condition in newborns, said Cynthia Powell, MD, pediatric geneticist, UNC site principal investigator for Early Check.

Results No Parent Wants to Hear

When their baby was three-weeks-old, the parents registered their son to be a part of the study. Four days later, they received a phone call.

It was one of those really nice spring days, a Friday afternoon. We were out getting ice cream and when we got back in the car, we both had missed calls. After listening to the voicemail, my stomach dropped, the mom said.

Their son received an abnormal newborn screening result for SMA, a rare genetic disorder caused by deficiency of the survival motor neuron protein (SMN1), resulting in progressive degeneration and irreversible loss of cells in the spinal cord and brainstem. Without treatment, the decreased level of the SMN protein leads to muscle weakness, and wasting atrophy of muscles used for movement. Most babies diagnosed with this disorder will have weak mobility, typically shown in the extremities, such as limp legs and arms, before six-months of life. This debilitating and often fatal muscle weakness can lead to an individual not being able to perform the basic functions of life, like breathing and swallowing, eventually leading to death by two or three-years-old. SMA is the leading cause of infant mortality from a single gene disorder, and its prevalence is one per 10,000 births globally.

This is a pretty devastating genetic disease, said Zheng (Jane) Fan, MD, pediatric neurologist, co-investigator for the Early Check pilot study. The severity of the disease depends on the genetic mutation subtype. For SMA babies, they have no copies of the SMN1 gene. Their disease severity depends on the number of copies of the SMN2 gene, which serves as a backup copy for the SMN1 gene, she said.

The Early Check results showed that the son had an absent SMN1 gene. A follow-up appointment was scheduled for the family to visit UNC School of Medicines Clinical & Translational Research Center (CTRC) the following Tuesday for confirmatory testing and to see how many copies of the SMN2 gene were present. For the parents, it was a long, grueling three days full of questions about whether or not their son was going to live.

We basically mourned the loss of our son that entire weekend before our visit to Chapel Hill, said the dad.

The confirmatory testing tells how many copies of the SMN2 gene are present. If there are three or more copies of the SMN2 gene, a baby could have a moderate form of SMA, whereas if there are two or less copies of SMN2, it could lead to a more severe form. Results showed that the son had three back-up copies of the SMN2 gene.

All the types of SMA are caused by the same gene variant, but are different in severity that will influence the age of onset and how quickly and severe it will manifest. Classification is based on the clinical age of onset and rate of regression, said Yael Shiloh-Malawsky, MD, pediatric neurologist and associate professor in the UNC Department of Neurology. With the more severe form, a child will never gain the milestone of sitting. This is Type I. Type II are kids who will be able to sit, but will never gain independent walking and later on can lose the ability to sit without help. Type III are children who gain walking, and later on will have decline in their strength.

Just looking at the child with the naked eye, no one could tell that he had a debilitating disorder forming on the inside. No symptoms were shown at all. For this particular case, the son fell within the Type II range.

For babies with Type I or II, the recommendation is to start treatment as soon as possible, said Dr. Fan.

We didnt even think treatment was an option, said the mom as her eyes begin to fill with tears.

During our first appointment with Dr. Fan, she showed us videos of children jumping rope and running. Children who had SMA, but received treatment. We never thought our son was going to be able to do any of those things, her voice trembled.

Life-Saving New Treatments for SMA

New medical advances are changing the course of SMA by helping thousands of children diagnosed with the disease experience better outcomes. For this family specifically, treatments were narrowed down to two choices; Spinraza, an FDA approved drug at $125,000 per one dose that is continued every four months for the duration of the individuals life, or they could choose the recent FDA approved gene therapy called Zolgensma, a $2-million dollar one-time treatment.

Time was of the essence. With SMA, once symptoms start to appear, its a red flag that motor neurons have already been lost. A decision needed to be made quickly.

After discussions with our pediatrician, Dr. Fan, Dr. Shiloh, and other medical professionals, we decided to choose Zolgensma, said the mom.

Zolgensma, the first gene therapy approved to treat children with SMA less than two-years-old, is a one-time intravenous infusion that takes about an hour. It involves a safe virus, AAV9, that delivers a fully functional human SMN1 gene to the targeted motor neurons, which in turn improves muscle movement and function, and also improves survival and quality of life.

Multiple testing went underway to see if the child was eligible for the Zolgensma treatment.

If the baby had antibodies against the AAV9 virus, then the gene therapy wouldnt have been effective, Dr. Fan said. This is because once the therapy penetrates the blood, the antibodies would kill the virus, even though the virus was harmless and carrying potentially life-saving cargo.

Luckily, test results showed that the baby did not have antibodies against the virus. It took two weeks for the treatment to be approved from insurance and to be delivered to UNC Childrens Hospital. Then on April 21st at eight-weeks-old, the baby became the first at UNC Medical Center to receive the life-saving gene therapy treatment.

I have a real appreciation for our doctors. They are so brilliant and they want to use that towards the good of our children. Theres hope, said the dad.

From checking in, receiving the treatment, to monitoring for side effects, the whole process took about seven hours. After staying in town for a couple days, the family headed back home. However, the son was monitored continuously to check for potential side effects the biggest being elevated liver enzymes, due to an inflammatory response.

This baby tolerated the gene therapy treatment well, with no apparent side effects and his liver enzymes remained in normal range throughout the monitoring period, Dr. Fan said.

For children diagnosed with SMA Type II, muscle weakness develops between ages 6 and 12 months. However, because the Early Check newborn screening was available for SMA and the child received the gene therapy early before the onset of symptoms, the outcome is in his favor.

If the child had been born in a different state that already started newborn screening on a population basis, he would have been screened, but because North Carolina hadnt started screening for SMA yet, he wouldve been missed if his family hadnt signed up for the study. Its pretty remarkable, said Dr. Powell.

As of May 1, 2021, SMA has been part of newborn screening statewide, and North Carolina is among the more than 30 states with this screening.

Our expectation is that this child will have normal development, normal strength like any other baby, said Dr. Shiloh-Malawsky.

For now, the parents continue to be observant of their son while being cautiously optimistic.

Its the nature of parenting that youre going to worry about your child, said the mom. I was thinking it was a death sentence when I heard about my sons diagnosis. Were only three months into it, but from what the doctors have said, it doesnt have to be a death sentence. My son can live a fulfilling life. Were grateful for that.

So far, hes right on track for his physical therapy evaluation, and recently, he rolled over for the very first time, she said, and she smiled.

Written by Brittany Phillips, UNC Health Communications Specialist

Read more from the original source:
Baby First at UNC to Receive Gene Therapy for SMA, Thanks to Early Check Newborn Screening | Newsroom - UNC Health and UNC School of Medicine