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Category Archives: Genetic Medicine

Taysha Gene Therapies Announces Collaborations to Advance Next-Generation Mini-Gene Payloads for AAV Gene Therapies for the Treatment of Genetic…

DALLAS--(BUSINESS WIRE)--Taysha Gene Therapies, Inc. (Nasdaq: TSHA), a patient-centric, clinical-stage gene therapy company focused on developing and commercializing AAV-based gene therapies for the treatment of monogenic diseases of the central nervous system (CNS) in both rare and large patient populations, today announced multi-year collaborations with Cleveland Clinic and UT Southwestern Gene Therapy Program (UTSW) to advance next-generation mini-gene payloads for AAV gene therapies for the treatment of genetic epilepsies and additional CNS disorders. Taysha will have an exclusive option on new payloads, constructs and intellectual property associated with, and arising from, the research conducted under this agreement.

A team of researchers from Cleveland Clinic Lerner Research Institute will create mini-gene payloads designed to address some of the long-standing limitations in AAV gene therapy. UTSW will create and evaluate vector constructs in in vivo and in vitro efficacy models of genetic epilepsies and additional CNS disorders.

By pushing the boundaries of AAV vector engineering, we may be able to overcome some of the challenges inherent with gene therapy and potentially expand the range of treatable genetic CNS diseases with gene therapies. We appreciate the support from Taysha and UTSW in this work, said Dennis Lal, Ph.D., Assistant Staff at Cleveland Clinic Genomic Medicine Institute and Neurological Institute. We believe that our proprietary approach to overcoming current limitations of packaging capacity and our access to data on thousands of protein structures associated with a whole host of monogenic CNS disorders has the potential to enable a deep pipeline of functioning mini-genes.

Cleveland Clinic and UTSW are two of the worlds preeminent leaders in gene therapy innovation, and this collaboration is designed to leverage our capabilities and synergies with these institutions to pioneer novel approaches to address vector capacity, which is a common limitation when treating genetic disorders associated with large proteins, said Suyash Prasad, MBBS, M.SC., MRCP, MRCPCH, FFPM, Chief Medical Officer and Head of Research and Development of Taysha. We look forward to a productive collaboration with the goal of developing treatments with promising benefits to patients with debilitating genetic epilepsies.

About Taysha Gene Therapies

Taysha Gene Therapies (Nasdaq: TSHA) is on a mission to eradicate monogenic CNS disease. With a singular focus on developing curative medicines, we aim to rapidly translate our treatments from bench to bedside. We have combined our teams proven experience in gene therapy drug development and commercialization with the world-class UT Southwestern Gene Therapy Program to build an extensive, AAV gene therapy pipeline focused on both rare and large-market indications. Together, we leverage our fully integrated platforman engine for potential new cureswith a goal of dramatically improving patients lives. More information is available at http://www.tayshagtx.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as anticipates, believes, expects, intends, projects, and future or similar expressions are intended to identify forward-looking statements. Forward-looking statements include statements concerning or implying the potential of our collaboration with the Cleveland Clinic and UTSW, the potential of our product candidates to positively impact quality of life and alter the course of disease in the patients we seek to treat, our research, development and regulatory plans for our product candidates, the potential benefits of rare pediatric disease designation and orphan drug designation to our product candidates, the potential for these product candidates to receive regulatory approval from the FDA or equivalent foreign regulatory agencies, and whether, if approved, these product candidates will be successfully distributed and marketed. Forward-looking statements are based on managements current expectations and are subject to various risks and uncertainties that could cause actual results to differ materially and adversely from those expressed or implied by such forward-looking statements. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. Risks regarding our business are described in detail in our Securities and Exchange Commission (SEC) filings, including in our Quarterly Report on Form 10-Q for the quarter ended September 30, 2020, which is available on the SECs website at http://www.sec.gov. Additional information will be made available in other filings that we make from time to time with the SEC. Such risks may be amplified by the impacts of the COVID-19 pandemic. These forward-looking statements speak only as of the date hereof, and we disclaim any obligation to update these statements except as may be required by law.

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UAB-developed research tool will help scientists better understand COVID-19 – Alabama NewsCenter

UAB has developed a database that promises to be an important tool in fighting COVID-19. PAGER-CoV is packed with nearly 12,000 pieces of genetic information on the SARS-CoV-2 virus, information that researchers and physicians can use to tailor treatments against the disease.

PAGER-CoV is an extension of PAGER, a database of gene sets created by Jake Chen, professor in the UAB Department of Geneticsand associate director of the Informatics Institute in the School of Medicine. Chen created PAGER 10 years ago at Indiana University. As the pandemic spread in early 2020, Chen and his UAB colleagues created a similar system, PAGER-CoV, in response.

The database includes 11,835 PAGs, which stands for pathways, annotated gene lists and gene signatures.

Pathways form a roadmap that describes how genes are turned on and off and how they establish connections with each other.

Annotated gene lists are empirical information that researchers collect from experiments or literature. Gene lists help researchers understand how a certain cell type behaves under different conditions.

A gene signature is a unique pattern of gene expression within a cell from a single gene or group of genes, providing information about the activity of those genes.

SARS-CoV-2 is a new virus, and we didnt know much about its function back in the summer of 2020, Chen said. The goal here is to gather all this information together in a searchable database so that researchers can gain a better understanding of how the viruss genes behave or perform under various biophysical conditions, such as severe COVID-19 or long-haul COVID-19 patients.

Chen said SARS-CoV-2 has 15 genes, with scant information on how they affect human cells.

We need to understand the differences in people who die from COVID-19 versus the person who only has a mild case of the disease, he said. This is a precision medicine approach, employing the database to organize all that weve learned about the virus so that the information can be used in an effective way.

Chen said the downstream effects of coronavirus are not well understood. Better understanding could lead to tailored therapeutics based on gene behavior.

We need to know how the virus proteins are interacting with human cells, and we need to know what we can do about it, he said. There is no shortage of possible therapeutics. There is a shortage of regimens that will pair the right therapeutic with the right person. Precision data-driven medicine is what this work will help COVID-19 physicians understand.

Chens and his colleagues paper on the workings of PAGER-CoV was published in January in Nucleic Acids Research. The team searched the medical literature for all articles dealing with the SARS-CoV-2 virus. They then used super computers that employed data science tools to do comprehensive data processing and integration.

Chen said users can search the database with any human gene or a PAG of interest, drill down to their database entry and navigate to other related PAGs through either shared PAG-to-PAG co-membership relationships or PAG-to-PAG regulatory relationships. To date, there are nearly 20 million PAG-to-PAG relationships in the database.

Our intent is to provide a resource that researchers doing functional genomic studies of COVID-19 will use, Chen said. There is a lot of information here, organized in a way that we hope will spur new insights and lead to meaningful results.

PAGER-CoV will grow as new information is available and added to the database. Chen urges researchers worldwide to use the portal and participate in this community-based knowledge curation effort.

PAGER-CoV is freely available to the public without registration or login requirements (http://discovery.informatics.uab.edu/PAGER-CoV/). The data is available for download based on the agreement of citing this work while using the data from the PAGER-CoV website.

Joint first authors on the paper are Zongliang Yue and Eric Zhang. Additional co-authors are Clark Xu, Sunny Khurana, Nishant Batra, Son Do Hai Dang and James J. Cimino.

PAGER-CoV was developed with support from the UAB Informatics Institute, Academic Enrichment Fund, Center for Clinical and Translational Science, and the National Cancer Institute and National Center for Advancing Translational Sciences of the National Institutes of Health.

This story originally appeared on the University of Alabama at BirminghamsUAB News website.

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UAB-developed research tool will help scientists better understand COVID-19 - Alabama NewsCenter

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MD Anderson and Mirati Therapeutics announce KRAS strategic research and development collaboration in solid tumors – Newswise

Newswise HOUSTON and San Diego, Calif The University of TexasMD AndersonCancer Center and Mirati Therapeutics, Inc. today announced a strategic research and development collaboration to expand the evaluation of Miratis two investigational small molecule, potent and selective KRAS inhibitors adagrasib (MRTX849), a G12C inhibitor in clinical development, and MRTX1133, a G12D inhibitor in preclinical development, as monotherapy and in combination with other agents which target two of the most frequent KRAS mutations in cancer.

The collaboration will combineMD Andersonsclinical trial infrastructure and expertise with Miratis differentiated targeted oncology pipeline. Under the terms of the agreement, collaborative preclinical and clinical studies will be conducted in several solid tumors, including non-small cell lung, pancreatic, colorectal and gynecological cancers over the five-year period of the collaboration.

This agreement embodies our commitment to further advancing our innovative KRAS programs and complementing our development efforts through strategic collaborations with those who share our vision for breakthrough science, said Joseph Leveque, M.D., Executive Vice President and Chief Medical Officer, Mirati Therapeutics. We look forward to working with MD Anderson to strengthen our scientific and clinical understanding of KRAS compounds in multiple tumor types with the goal of speeding delivery of new cancer treatments to patients.

The collaborative studies will be overseen by a joint steering committee. Mirati will provide funding, study materials and other ongoing support throughout the term of the collaboration.

Effective targeted therapies against mutant KRAS could address a major unmet need for many patients, said Christopher Flowers, M.D., ad interim division head of Cancer Medicine at MDAnderson. Our collaboration with Mirati represents an important opportunity to work toward advancing new treatment options for patients using novel KRAS inhibitors that target two of the most frequent KRAS mutations in common cancers.

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About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. The institutions sole mission is to end cancer for patients and their families around the world. MD Anderson is one of only 51 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is ranked No.1 for cancer care in U.S. News & World Reports Best Hospitals survey. It has ranked as one of the nations top two hospitals for cancer care since the survey began in 1990 and has ranked first 16 times in the last 19 years. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).

About Mirati Therapeutics

Mirati Therapeutics (NASDAQ: MRTX) is a San Diego-based late-stage biotechnology company relentlessly focused on translating drug discovery and research into new treatments for patients by advancing and delivering novel therapeutics that target the genetic and immunologic drivers of cancer. Mirati is advancing a novel pipeline to treat large patient populations across multiple programs and tumor types, including two programs, adagrasib and sitravatinib, in registration-enabling studies to treat non-small cell lung cancer (NSCLC).

Adagrasib is an investigational small molecule, potent and selective KRAS G12C inhibitor in clinical development as a monotherapy and in combinations. MRTX1133 is an investigational small molecule, potent and selective KRAS G12D inhibitor in preclinical development.

Sitravatinib is an investigational spectrum-selective inhibitor of receptor tyrosine kinases (RTK) designed to enhance immune responses through the inhibition of immunosuppressive signaling. Sitravatinib is being evaluated in multiple clinical trials to treat patients who are refractory to prior immune checkpoint inhibitor therapy, including a Phase 3 trial of sitravatinib in combination with nivolumab in NSCLC.

For more information about Mirati, visit http://www.mirati.com or visit us on LinkedIn.

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MD Anderson and Mirati Therapeutics announce KRAS strategic research and development collaboration in solid tumors - Newswise

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[Full text] The Associations Between Vitamin D Receptor BsmI and ApaI Polymorphism | DMSO – Dove Medical Press

Introduction

Obesity is a common metabolic disorder and its prevalence is increasing worldwide.1 In Korea, the prevalence of obesity is rapidly increasing because of westernized diet and sedentary lifestyle; consequently, it has become a serious socioeconomic problem.2 According to an obesity fact sheet of Korea, the occurrence of obesity in adults increased from 29.7% in 2009 to 35.7% in 2018.3 Further, obesity is closely associated with increased risks of various chronic metabolic disorders, including diabetes mellitus (DM), hypertension, dyslipidemia, and cardiovascular diseases.1 According to the diabetes fact sheet in Korea, half of the patients with DM suffer from obesity.4 Therefore, the assessment and management of obesity is important to reduce obesity-related complications in a population.

Obesity results from the interactions between environmental and genetic factors. A previous study reported that genetic factors are responsible for approximately 4070% of the etiology of obesity.5 Moreover, advanced technologies such as genome-wide association studies have led to the identification of some candidate obesity-related genes.6

The vitamin D endocrine system plays a central role in bone and calcium homeostasis. Apart from its classical involvement, vitamin D also plays an important role in other metabolic pathways in immune system, cancers, and other endocrine systems.7 Although vitamin D deficiency has been associated with obesity,8,9 the exact underlying mechanisms leading to obesity have not been fully determined yet; regardless, some possible explanations, such as insulin resistance and lipolysis have been suggested.10

Vitamin D receptor (VDR; a member of the steroid/thyroid hormone receptor superfamily)11 in complex with vitamin D serves as a transcription activator and regulates gene transcription by binding to vitamin D responsive elements, which are located in the promoter region of the target genes. Therefore, genetic alterations of VDR gene can alter gene activation, and lead to various diseases.7 Furthermore, VDR gene is also expressed in adipocytes and pancreatic beta cells linked to insulin resistance and therefore it might be associated with body composition as well.12,13 More than 470 VDR polymorphisms have been identified in the VDR gene.14 Among them, the well-established VDR polymorphisms are as follows: FokI (rs2228570 C > T), BsmI (rs1544410 A > G), ApaI (rs7975232 C > T), TaqI (rs731236 T > C), and Cdx2 (rs11568820 A > G).15 A previous study has demonstrated that TaqI and BsmI polymorphisms are associated with obesity in French patients with type 2 diabetes mellitus (T2DM).16 In another study performed in the Thai population, the Cdx2 polymorphism was associated with a higher waist circumference; however, the four common polymorphisms (FokI, BsmI, ApaI, and TaqI) of the VDR gene did not show any association with BMI.17 In contrast, the VDR BsmI polymorphism has shown a significant association with vitamin D deficiency but not with the obesity phenotype in adolescents residing in Malaysia.8

So far, the previous studies have shown inconsistent results pertaining to the associations between VDR polymorphisms and obesity. Furthermore, there is a lack of data regarding the same in the Korean population, especially the data of patients with T2DM who have a higher risk of obesity. Therefore, in this study, we evaluated the association between BsmI and ApaI polymorphisms of the VDR gene and obesity in Korean patients with T2DM.

This was a single-center, casecontrol study. Patients who were diagnosed with T2DM and treated at the Chungbuk National University Hospital, Korea, were included in the study. The diagnosis of T2DM was performed by the World Health Organization criteria. Patients with type 1 DM and other types of DM were excluded from this study. The demographic data including age, sex, height, weight, BMI, duration of DM, and family history of DM were collected through reviewing of medical records. Further, the laboratory data, such as fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), C-peptide, insulin, and liver function, kidney function, and lipid metabolism parameters, were also investigated for each patient.

BMI was used to evaluate obesity. The BMI (kg/m2) was calculated as baseline body weight (kg) divided by the square of the height (m2). Obesity was defined as a cutoff value of 25 kg/m2 BMI, according to Asian-Pacific guidelines.18

The two polymorphisms of VDR, BsmI and ApaI, were analyzed in this study. Peripheral leukocytes were isolated from ethylenediaminetetraacetic acid-treated whole blood obtained from each patient. Then, the genomic DNA was extracted for subsequent polymerase chain reactions (PCR). All the included T2DM patients were genotyped using PCR-restriction fragment length polymorphism method, for two restriction sites in the VDR gene, BsmI and ApaI using specific primer sequences. The following BsmI and ApaI primers were used for amplification: (BsmI) forward 5-CAA CCA AGA CTA CAA GTA CCG CGT CAG TGA-3 and reverse 5-AAC CAG CGG AAG AGG TCA AGG G-3. (ApaI) forward 5- GGG ACG CTG AGG GAT GGC AGA GC-3 and reverse 5-GGA AAGGGGTTAGGTTGGACAGGA-3. The primers of the VDR gene were designed based on previous literature.19 The PCR condition used for Bsm I as followed: an initial denaturation of 3 min at 94 C, followed by denaturation of 30 s at 94 C, annealing of 30 s at 62 C, and extension of 1 min at 72 C for 30 cycles, and a final extension of 5 min at 72 C. The PCR condition used for amplification of Apa1 as follows; 94 C for 10 min, and 30 cycles using the following temperature profile: 94 C for 1 min, 62 C for 1 min, 72 C for 1 min, and final elongation for 5 min. The PCR products were digested overnight at 37 C by Fermentas restriction enzymes, and then resolved in 1.5% agarose gel electrophoresis for the genotype analysis. We analyzed three genotypes for each polymorphism: BB, Bb, and bb for BsmI and AA, Aa, and aa for ApaI.

The probability of HardyWeinberg equilibrium was tested using the chi-squared test. The data were expressed as the mean standard deviation or as percentages for the categorical variables. The baseline characteristics were compared using Students t-test for the continuous variables and chi-squared test for categorical parameters. Multiple logistic regression analyses were performed to evaluate the relationship between obesity and the following variables: genotype, sex, age, duration of DM, hypertension, dyslipidemia, and HbA1c. All statistical analyses were performed using SPSS for Windows software 22.0 (IBM Corp., Armonk, NY, USA). The significance was set at P < 0.05.

The study was approved by the International Review Board of Chungbuk National University Hospital (IRB No. 201803-034-001) and conducted in accordance with the Declaration of Helsinki. All procedures were carried out with adequate understanding, and all patients gave their informed consent prior to being included in the study.

A total of 506 patients (266 males and 240 females) were included in this study. The demographic and biochemical characteristics of the patients are shown in Table 1. The mean age and BMI of the patients were 62.6 10.6 years and 25.1 3.5 kg/m2, respectively. The mean duration of DM was 14.7 7.5 years and approximately 51% of the patients had a family history of DM. The mean HbA1c and FPG values were 7.6 1.4% and 145.1 55.4 mg/dL, respectively. The patients were categorized into obesity group and normal weight group depending upon their BMI values. The mean BMI was 27.9 2.9 kg/m2 in the obesity group and 22.7 1.7 kg/m2 in the normal weight group (P <0.001). The proportion of females and prevalence of hypertension and dyslipidemia were higher in the obesity group than in the normal weight group. The duration of DM was shorter in the obesity group than in the normal weight group; however, family history of DM and serum HbA1c levels did not show significant differences between the two groups. The serum triglyceride levels were 172.6 120.3 mg/dL in the obesity group and 146.0 78.0 mg/dL in the normal weight group (P = 0.004). Finally, the liver enzymes, including aspartate aminotransferase (AST) and aspartate aminotransferase (ALT), were significantly higher in the obesity group than in the normal weight group.

Table 1 Baseline Characteristics of the Patients

Table 2 presents various parameters according to BsmI genotypes. Patients with the bb genotype (bb group) showed significantly higher BMI (25.2 3.5 kg/m2) than patients with BB or Bb genotypes (BB + Bb group; 24.1 3.1 kg/m2; P = 0.034). However, no significant differences were observed between the glucose metabolism, lipid metabolism, and liver enzyme parameters of the two groups.

Table 2 Various Parameters According to BsmI Genotypes

The clinical parameters according to ApaI genotypes are shown in Table 3. The mean BMI was 25.1 3.5 kg/m2 in patients with the Aa or aa genotypes (Aa + aa group) and 24.1 2.4 kg/m2 in patients with AA genotype (AA group); however, the difference was not significant (P = 0.180). Other laboratory findings were not significantly different between these two groups.

Table 3 Various Parameters According to ApaI Genotypes

The frequencies of BsmI genotypes in the patients were as follows: BB, 2.0% (n = 10); Bb, 10.3% (n = 52); and bb, 87.7% (n = 444). The frequencies of the ApaI genotypes in the patients were as follows: AA, 4.5% (n = 23); Aa, 46.8% (n = 237); and aa, 48.6% (n = 246; Supplementary Table 1). The bb group was significantly associated with a higher prevalence of obesity compared with the BB + Bb group (48.4% vs 33.9%; P = 0.031; Table 4). Moreover, the Aa + aa group showed a higher prevalence of obesity than the AA group (47.6% vs 26.1%; P = 0.043; Table 4). Furthermore, we performed a logistic regression analysis of the risk factors associated with obesity, and the related data are shown in Table 5. The non-B allele of BsmI was significantly associated with obesity, and the odds ratio (OR) was 2.132 (P = 0.014). The a-allele of ApaI also showed a significantly high risk of obesity (OR was 2.711, P = 0.048). Among other parameters, female sex, hypertension, and dyslipidemia were identified as the risk factors for obesity.

Table 4 Association Between Genotypes of VDR Polymorphisms and Obesity

Table 5 Logistic Analysis of Risk Factors to Determine Their Association with Obesity According to VDR Polymorphisms

In this study, we investigated the association between BsmI and ApaI polymorphisms in VDR gene and obesity in Korean patients with T2DM. We found that patients with T2DM carrying the bb genotype of VDR BsmI polymorphism were associated with higher BMI and increased risk of obesity than the BB or Bb genotypes. Although patients with the Aa or aa genotypes did not show significant differences in BMI (compared with the patients with AA genotype), the a-allele showed a significant correlation with obesity in the study population.

Recently, non-classical roles of vitamin D such as regulation of hormone secretion, immune function, cellular proliferation, and differentiation have emerged.20 Interestingly, previous studies have associated the effects of vitamin D with obesity. For instance, in a study of mixed-ethnicity participants, the individuals with obesity and those who were overweight showed a significant inverse correlation of serum 25-hydroxyvitamin D (25(OH)D) level with body weight, BMI, and waist circumference.21 Another study demonstrated that vitamin D affects energy expenditure through the upregulation of leptin gene expression.22 Further, the previous meta-analysis has reported that vitamin D deficiency is associated with obesity.23 Moreover, vitamin D improves insulin sensitivity; therefore, vitamin D deficiency may lead to the development of T2DM.24,25 Thus, these studies imply that vitamin D may play a possible role in obesity and obesity-related metabolic disorders.

Vitamin D binds to VDR to induce transcription pathways and gene expression. Therefore, genetic alterations of the VDR gene may hinder the gene activation and functions.7 As VDR expression has been found in adipose tissues, the association between obesity and VDR polymorphisms has also been investigated.8,9,16 In a study performed in French subjects with T2DM, BsmI and TaqI polymorphisms were associated with obesity; whereas ApaI did not show any significant correlation.16 This is in accordance with the results of our study. Another study showed that BsmI polymorphism was significantly associated with a higher BMI.26 Interestingly, conflicting results have been observed with respect to the association of obesity and ApaI polymorphisms. In a Chinese population, positive associations were observed between ApaI polymorphism and obesity (assessed by body fat percentage and skinfold thickness).27 In contrast, these associations were not observed in another study, which involved a study group of young Chinese males.28 In adolescents and young adults from Spain and Malaysia, no significant associations were observed between the VDR gene polymorphisms and obesity-related phenotypes.8,9 In recently published data, ApaI polymorphism appears to be correlated with overweightness and obesity in Chinese children.29 There are many ongoing studies and new SNP in VDR gene (rs3847987) have been shown an association with obesity phenotypes.30 Thus, to date, inconsistent results have been observed with respect to VDR polymorphisms and obesity. We believe that these differences may be attributed to different parameters such as sex, age, ethnicity, and behavioral characteristics. Further studies are needed and obesity is closely related to the development of T2DM and has been attributed to the progression of diabetic complications via various mechanisms.31,32 Therefore, it is possible that VDR polymorphisms, which are related to obesity, may be responsible for these complications in patients with T2DM. Previous studies have reported an association between VDR polymorphisms and diabetic complications.33,34 Results from the logistic regression analysis showed that BsmI and ApaI polymorphisms were strong risk factors for obesity. Thus, our data imply a possible effect of VDR polymorphisms on obesity in patients with T2DM, which is in accordance with the results of previous studies.16,26

To our knowledge, this is the first study to assess the association between the VDR polymorphisms and obesity in Korean patients with T2DM. The present study was performed in relatively homogenous subjects with similar ethnicities and disease statuses. However, there are several limitations of our study. First, we did not evaluate the serum 25(OH)D level, therefore, we could not determine whether the patients had vitamin D deficiency. Second, the clinical characteristics related to obesity such as physical activity and diet were not evaluated. Moreover, other parameters assessing obesity including waist circumference and body composition could not obtain due to the retrospective study design. Third, there was no control group of individuals without T2DM. Finally, not all VDR polymorphisms were investigated. Thus, we cannot rule out that other VDR polymorphisms may also be associated with obesity in the studied population.

In conclusion, the present study demonstrated that BsmI and ApaI polymorphisms of the VDR gene were associated with obesity in Korean patients with T2DM. However, further studies with larger multiethnic cohorts and experimental models are required to validate our results.

Parts of this study were presented at the International Congress on Obesity and Metabolic Syndrome, Seoul, Korea, 69 September 2018.

All retrospective data involving human participants were in accordance with the ethical standards and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Ethical approval was obtained by the Local Ethics Committee.

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. Everyone participated in the final approval of the manuscript.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The authors received no funding and report no conflicts of interest for this work.

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19. Eltahir Khalid K. Vitamin D receptor gene polymorphisms in Sudanese children with type 1 diabetes. AIMS Genetics. 2016;3(3):167176. doi:10.3934/genet.2016.3.167

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23. Manousopoulou A, Al-Daghri NM, Garbis SD, Chrousos GP. Vitamin D and cardiovascular risk among adults with obesity: a systematic review and meta-analysis. Eur J Clin Invest. 2015;45(10):11131126. doi:10.1111/eci.12510

24. Teegarden D, Donkin SS. Vitamin D: emerging new roles in insulin sensitivity. Nutr Res Rev. 2009;22(1):8292. doi:10.1017/S0954422409389301

25. Palomer X, Gonzalez-Clemente JM, Blanco-Vaca F, Mauricio D. Role of vitamin D in the pathogenesis of type 2 diabetes mellitus. Diabetes Obes Metab. 2008;10(3):185197. doi:10.1111/j.1463-1326.2007.00710.x

26. Hasan HA, AbuOdeh RO, Muda W, Mohamed H, Samsudin AR. Association of vitamin D receptor gene polymorphisms with metabolic syndrome and its components among adult Arabs from the United Arab Emirates. Diabetes Metab Syndr. 2017;11(Suppl 2):S531S537. doi:10.1016/j.dsx.2017.03.047

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Precision NanoSystems Receives Contribution from the Government of Canada to Build RNA Medicine Biomanufacturing Centre – PRNewswire

"Our government is bringing back the vaccine manufacturing capacity that Canadians expect and need. These investments will help to ensure that Canada has modern, flexible vaccine manufacturing capabilities now and in the future. With the investments announced today, our government is helping Canadian companies advance made-in-Canada vaccines and therapies, while securing domestic manufacturing options for international vaccine candidates. This is all part of our government's commitment to protect the health and safety of all Canadians today, and in the future", said the Honourable Franois-Philippe Champagne, Minister of Innovation, Science and Industry.

PNI supports the development of genetic medicines by providing products and services to its clients worldwide who are creating new treatments for infectious diseases, rare diseases, cancer and other areas of unmet need. This project will help PNI establish a Biomanufacturing Centre that will expand Canada's epidemic and pandemic preparedness capacity and will enable PNI to expand its development and manufacturing services to support the clinical development and supply of new medicines.

"PNI's centre of manufacturing excellence of nanomedicine will be a state-of-the-art facility for the development and manufacture of genetic therapeutics and vaccines," James Taylor, CEO, Precision NanoSystems stated. "The centre will continue Canada's leadership in the creation of innovative solutions for the development and production of new medicines for the benefit of patients in Canada and beyond. This support from the Government of Canada helps PNI to further achieve our mission of accelerating the creation of transformative medicines that significantly impact human well-being."

About Precision NanoSystems Inc. (PNI)

PNI is a global leader in ushering in the next wave of genetic medicines in infectious diseases, cancer and rare diseases. We work with the world's leading drug developers to understand disease and create the therapeutics and vaccines that will define the future of medicine.PNI offers proprietary technology platforms and comprehensive expertise to enable researchers to translate disease biology insights into non-viral genetic medicines.

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http://www.precisionnanosystems.com

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Africans begin to take the reins of research into their own genomes – Science Magazine

Volunteers in rural Uganda provided blood samples and health information for the biggest genomics effort in Africa, the Uganda Genome Resource.

By Elizabeth PennisiFeb. 4, 2021 , 2:15 PM

In 1987, 10-year-old Segun Fatumo was on the streets of Lagos, Nigeria, hawking palm oil, yams, and pepper each day after school to help put food on the table. In the evenings, he and his family crowded into a two-room dwelling without running water or electricity. He knew nothing of the plan being hatched by U.S. and U.K. geneticists to sequence the human genome.

Thirteen years later, when researchers completed the draft sequence of the human genome, Fatumothen an undergraduate studying computer scienceheard all about it. I knew the project would change our world, he recalls. What he didnt realize at the time was how it would change his life.

Fast forward more than 2 decades. Fatumo is now a computational geneticist in Entebbe, Uganda, with the Medical Research Council/Uganda Virus Research Institute and the London School of Hygiene & Tropical Medicine. Genome data by the terabytes flow through his seven-person lab, which is working to pinpoint genes involved in heart, kidney, and other diseases. All members of his team are African, the data come from African donors, and the ultimate goal is to improve the health of the people of Africa.

Until recently, genetic research in Africa was scanty, and most was done by researchers swooping in from afar to gather samples, then leaving to do analyses in well-equipped labs in the United States or Europe. African genomic study was characterized by ethical dumping, helicopter science, and exploitation, Fatumo says. Researchers gathered samples with little regard for informed consent and without giving back to the communities they studied, he says.

Today, Fatumo and scores of other young Africans are doing a substantial and growing share of this research. African genomics is a story thats going to be told more and more by Africans, says Charles Rotimi, a genetic epidemiologist at the U.S. National Human Genome Research Institute (NHGRI).

Bolstered by the internationally funded Human Heredity & Health in Africa (H3Africa) Initiative, which sponsored Fatumo as a postdoc, these researchers hope to one day use their data to bring genetically tailored medicine to people who in some places still struggle to get electricity and basic health care. The work is beginning to close a wide gap in who benefits from the human genome revolution. Theres this genomics expansion across the world, says Neil Hanchard, molecular geneticist at Baylor College of Medicine. Why should Africa be left behind?

Genomewide association studies (GWAS) scan genome data for links to diseases. But the DNA in such studies mostly comes from white people.

(GRAPHIC) K. FRANKLIN/SCIENCE; (DATA) G. SIRUGO et al., CELL, 177, 1, 26 ( 2019)

Including African populations is also paving the way for a better understanding of the links between disease and genes in everyone, everywhere, because Africa holds more genomic diversity than any other continent. The African genome should be used as the reference genome for the entire world, says Tesfaye Mersha, a geneticist at the University of Cincinnati.

But genomic research in Africa has a long way to go. Researchers have only studied between 5000 and 10,000 whole genomes from Africans, compared with as many as 1 million worldwide. Africa has received less than 1% of the global investment in genomics research and clinical studies, Mersha says.

Whats more, funding for all current projects in H3Africa, a $176 million program supported by the U.S. National Institutes of Health (NIH) and the Wellcome Trust that has jump-started African genomics, is set to end in 2022. Fatumo has corralled another prestigious fellowship, but researchers across the continent are scrambling to make sure the nascent genomics community can surviveand grow.

Fatumo decidedhe wanted to study genetics as a youngster, after a doctor explained sickle cell disease to him. His brother suffered weeklong bouts of pain from the condition. Fatumo learned that his brother had two copies of the responsible geneand that he himself would be spared because he had just one copy. The role genes play in disease got me thinking, he recalls.

Sickle cell, which is nowbeing treated through gene therapy, is a classic example of how genetic knowledge can inform medical practice. And it primarily affects people of African descent. Yet most sickle cell studies and medical advances have happened in rich countries. Fatumo wants more Africans doing such research in the future.

One of six children, whose father worked as an unskilled tailor and later as a subsistence farmer and bush hunter, Fatumo moved with his family to the outskirts of Lagos when he was 9 years old. He hiked 2 kilometers early every morning to retrieve water from a river, wielded hoe and cutlass to tend crops, trekked to Lagos for school, then topped off the day hawking.

He and his parents managed to pay the 105 Nigerian naira (about $1) per year for school, thanks, in part, to Fatumos hawking profits. Fatumo says poverty fueled in him a fierce determination to do better. The story of my upbringing is the one that propels anger for success.

Computational geneticist Segun Fatumo studies the genomics of kidney, heart, and other diseases.

Later, he earned a B.S. in computer science at the African University of Science and Technology in Abuja, Nigeria. Because little genetics was being done at African universities, he pursued graduate degrees in computer science at Covenant University in Ota, Nigeria. I was lucky to study at Covenant where they had some key resources and constant electricity, he recalls. Even so, his bioinformatics analyses kept crashing the schools computer system. He spent 1 year studying in Heidelberg, Germany, where the same analysis was completed in less than 30 minutes with high-performance computers.

But he was working his way through school at the right time, in the right place. In 2009, the founders of the 6-year-old African Society of Human Genetics met in Cameroon to discuss their vision for an African genome project. It was a dream we had, but we didnt know where the funding would come from, Rotimi says. Francis Collins, who had coordinated the Human Genome Project but was then between jobs, was invited to give the opening talk.

He and other participants knew how much genomics studies in Africa could contribute to research worldwide. Trace any humans family tree back far enough and the roots wind up in Africa, where our species was born some 300,000 years ago. When some groups left the continent over the past 80,000 years or so and spread across the globe, they carried only a subset of human genomic diversity. As a result, the people of Africa today carry more genetic diversity than those of any other continent. There are parts of our genome that we cannot study any place beside Africa, says Rotimi, who directs NHGRIs Center for Research on Genomics and Global Health.

Those at the 2009 meeting also recognized that Africans needed to lead the way. The idea that people outside of Africa are going to be able to decide the priorities just doesnt work, Collins says. Local investigators are more likely to understand the culture and constraints and to be trusted by the community, Mersha adds.

Some researchers were skeptical about funding African-based research. People said the money would just disappear, Collins recalls. But I was pretty convinced we could step away from the colonial perspective where developed nations make the decisions. Collins became NIH director in 2009 and helped launch H3Africa in 2011. NIH has committed $150 million to the initiative through 2022, and Wellcome, a U.K. biomedical philanthropy giant, has kicked in another $26 million.

The initiative aimed to set up a network of laboratories across the continent to explore the relative roles of environment and genes in diseases that plague Africans, such as HIV/AIDS, trypanosome infections, stroke, diabetes, and heart disease. It also established biorepository and bioinformatics networks. To ensure a lasting legacy, it supports training as well as research.

In 2013,with H3Africa funding, Fatumo traveled to the Wellcome Sanger Institute in Hinxton, U.K., and the University of Cambridge as a postdoc in genetic epidemiology. At Sanger, he took part in the largest African genomics project to date, a multimillion-dollar effort to analyze genomic data from 14,126 people from five African countries, including newly collected whole genomes from nearly 2000 Ugandans. The international team of researchers found 9.5 million gene variants not previously spotted, underscoring the diversity of African populations and laying the groundwork for future genomic studies.

The results, published inCellin 2019, also included specific variants related to cardiovascular diseases in Africans, such as one previously linked to an inherited blood disorder called alpha thalassemia. That single variant could also shape the diagnosis of a third condition: It alters how sugars bind to red blood cells and so affects the results of the blood glucose test often used to track diabetes.

One year later, H3Africas milestone genome paper came out inNature. Human geneticist Zan Lombard and bioinformaticist Ananyo Choudhury from the University of the Witwatersrand, along with other African and international colleagues, analyzed 426 genomes, many newly sampled, from 50 populations in 13 countries. They described more than 3 million new human DNA variants, most from previously unsampled populations. The analysis also confirmed the continents complex migration patterns, tracing the path of Bantu-speaking people as they expanded southward and eastward more than 3000 years ago. That was just one of nearly 300 papers published so far by H3Africa teams, describing results as well as providing curated data sets of African genomes.

Researchers have only just begun to sample the genomes of Africa's 2000 ethnic groups and populations. A handful of whole-genome sequences in 2010 have grown to thousands from multiple projects, many of which are captured on the map below. Their distribution reveals huge gaps in genomic sampling across the continent.

Scroll over points on the map and legend items for more details

10500

> 500

Those databases will illuminate studies of human variation worldwide, in part because the great genomic diversity in Africans can uncover spurious links to medical conditions, explains Concepcion Nierras, an NIH Common Fund geneticist. For example, in Europeans a rare variant of a gene for a low-density lipoprotein that contributes to high cholesterol seemed to raise the risk of heart disease. But Fatumo and his colleagues found that among Africans, the variant was common even in those who did not have heart disease, suggesting it may not have clinical relevance. TheNaturepaper uncovered 54 such variants that now need re-evaluation.

Scientists say H3Africa has been thoughtful about ethics, vital in a continent with a long history of colonial exploitation and where such concerns remain a flashpoint. For example, until 2019 Sanger was working to develop a DNA chip for scanning African genomes quickly. But whistleblowers said study participantshadnt granted the institute permissionto use their DNA in this way. That chip is now not used, although one developed by H3Africa has become a mainstay.

To guard against exploitation, the project brought on bioethicists to discuss the research with local communities and figure out equitable partnerships, addressing concerns from populations worried about misuse of their data. They are also working to establish standards for effective, ethical informed consent. At Makerere University, orthopedic surgeon and bioethicist Erisa Mwaka Sabakaki and colleagues have reviewed hundreds of informed consent and other documents. Projects sometimes came up with unexpected solutions: For a study involving HIV-infected children, comic books proved a great way to communicate to both adults and children.

There are ongoing and important questions about informed consent, how best to engage communities, benefit sharing, stigma, and many other issues, says Jantina De Vries, a bioethicist at the University of Cape Town who helped set up H3Africas policies. But weve started on a really good trajectory.

Genome researchers work with Cameroonian volunteers to ensure informed consent.

H3Africas biggest achievement may be growing a generation of African genomicists, says Harvard University global public health expert Barry Bloom. The project has trained 137 Ph.D.s and 49 postdocs including Fatumo, as well as hundreds of masters students and undergraduates, and gives an incentive for scientists trained abroad to return to Africa. If not for H3Africa, maybe I wouldnt be a group leader and principal investigator today, Fatumo says.

These efforts have had spillover effects beyond human genetics. For example, the project helped train Christian Happi, a molecular biologist at Redeemers University in Ede, Nigeria, who runs the African Center of Excellence for Genomics of Infectious Diseases. His team quickly sequenced Nigerias first Ebola case, identified Lassa fever strains in a 2018 outbreak andin just 3 days in March 2020sequenced the first coronavirus genome from an African, showing SARS-CoV-2 had arrived from Europe.

The programs resources have enabled many African countries to respond to other health challenges, says Clement Adebamowo, a surgical oncologist at the University of Maryland School of Medicine who has been active in African genetics.

But H3Africassuccesses highlight how much more work is needed. Most of the projects genomes are from people of Southern, Central, and West African ancestry (see map, above), and many populations havent been sampled at all, including those in North Africa. Our studies combined are just the tip of the iceberg, says Sarah Tishkoff, a human geneticist at the University of Pennsylvania who has led the way in sampling remote populations.

Individual studies highlight how much more researchers need to know to understand the intersection of genes and disease. For example, an H3Africa project called the Collaborative African Genomics Network (CAfGEN) aims to come up with a blood test for HIV-positive newborns to show how quickly their infection could progress to AIDS. Researchers scrutinized the genomes of infected children, hoping to find genetic variants associated with slow HIV progression. Children with such variants could postpone treatment and reduce and delay long-term side effects.

But so far, the team has found just one piece of DNA, involved in the immune system, that varies significantly among the children. And candidate variants that popped up in a study of Botswanan children failed to appear in Ugandan children, underscoring the diversity of African genomes. The African genome is much more complex than we anticipated, says CAfGEN trainee Lesedi Williams, now a genomicist at the University of Botswana, Gaborone.

The sad reality is that genomics data from Africa [are] still too few, says geneticist Aim Lumaka of the University of Lige and the University of Kinshasa. So the medical significance of many variants in people of African descent is unknown.

Tishkoff and others are broadening their samples; this year she hopes to publish on 180 more African genomes, while Choudhury and his H3Africa colleagues are coming up with new places to sample, including Mauritius, Runion, and other islands.

More mundane challenges also loom. Our supply chains, financial systems, and infrastructure need strengthening, says Iruka Okeke, who studies pathogen genomes at the University of Ibadan. The continent is short of both sequencing capacity and computers powerful enough to analyze giant data sets. These impediments can lead H3Africa investigators to delay making data publicly available in order to do their own analyses, a practice that can create its own problems, says Steven Salzberg, a computational biologist at Johns Hopkins University. As long as each group keeps its data private, the next group that wants to study these populations has to start over and sequence a new cohort, he says.

With funding scarce, some H3Africa trainees are leaving human genetics for fields where research is cheaper. One CAfGEN trainee, Gerald Mboowa at Makerere University, has shifted away from human genomeswhich cost $1000 per sequenceto those of bacteria, which are a mere $90. He recently received a $100,000 Grand Challenges Africa grant funded by the Bill & Melinda Gates Foundation to track drug-resistant bacteria in hospitals.

Others, noting that direct health benefits from genes are often a long way off, wonder whether H3Africa money would be better spent on more immediate public health needs such as antismoking and healthy eating campaigns. In 2011 we didnt know whether H3Africa was the best way to spend international resources in Africa, says Richard Cooper, an emeritus epidemiologist at Loyola University Chicago who helped get the project off the ground. Unfortunately I [now] think the answer is in the negative, because genomics has yet to lead to many concrete boosts in health.

Fatumo is satisfied that his own work is of immediate benefit. As his organization gathered blood samples in rural Uganda, it discovered and treated diseases participants hadnt been aware of, including hepatitis and hypertension.

But a big challenge looms in 2022, when NIH Common Fund support ends. That loss could be a major blow to everything thats been built up, says Stefan Jansen, a psychologist at the University of Rwanda involved with an H3Africa project on posttraumatic stress disorder. Some support will come from another NIH program, Harnessing Data Science for Health Discovery and Innovation in Africa (DS-I Africa), which is slated to spend $62 million over the next 6 years. And an African genomics startup called 54Gene has gotten $15 million in international backing for a multimillion-dollar facility in Nigeria. But most H3Africa-supported researchers have had little luck finding funding within Africa. Its really, really challenging getting African funding from private companies or African governments, Rotimi says.

Some of Africas genomics researchers will manage to win new support from abroad, as Mboowa has done. Fatumo was recently awarded a highly competitive Wellcome International Intermediate Fellowship and now has $1.2 million over the next 5 years plus other support to explore genomic variants linked to chronic kidney disease; he hopes to develop risk scores based on patients genetic makeup.

He has also teamed up with a South African colleague and applied to become a DS-I Africa research hub. If successful, they will get $1.3 million per year for 5 years to use existing African genetic data to find and validate new drug targets.

Fatumo and others hope their generations accomplishments will lay the foundation for an even stronger research network. It is a great time for all of us doing genomics in Africa, Okeke says. The discovery potential is very high, and the impact that our work could have on health could be huge.

doi:10.1126/science.abg8903

Liz is a senior correspondent covering many aspects of biology forScience.

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