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Neutralizing Antibody & AAV FIX Gene Therapy

中和抗体

基本信息

批准号：
8415136
负责人：
RICHARD J SAMULSKI
金额：
$ 218.94万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-08 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8415136
关键词：
Address Animal Model Animals Antibody Formation Antigen Presentation Aptamer Technology Area Basic Science Binding Biochemistry Biological Biology Canis familiaris Capsid Cell Communication Cells Cellular biology Chronic Clinical Clinical Data Clinical Research Clinical Trials Development Disease Disease Progression Dose Engineering Ensure Epitopes Factor IX Future Gene Delivery Gene Expression Gene Transfer General Population Generations Goals Hematology Hemophilia A Hemophilia B Hemorrhage Hepatocyte Immune response Individual Instruction Joints Knowledge Liver Maps Modeling Molecular Molecular Biology Mus Patients Peptide Library Phenotype Philosophy Primates Program Research Project Grants Reagent Research Personnel Research Project Grants Resistance Role Safety Saint Jude Children&apos s Research Hospital Sampling Serum Surface Testing Therapeutic Tissues Transgenes Viral Viral Vector Virus Work adeno-associated viral vector aptamer arthropathies base design gene correction gene replacement gene therapy gene therapy clinical trial human disease in vivo interdisciplinary approach molecular vector mouse model neutralizing antibody next generation nonhuman primate novel prevent research study response sound success vector virology

项目摘要

DESCRIPTION (provided by applicant): The program project grant "Neutralizing Antibody (NAb) and AAV FIX Gene Therapy" is a timely focused application centered around advancing exciting new clinical data that "self complementary" (sc)AAV Factor IX (FIX) vectors are showing promising success in clinical studies (5-8% >1yr). To further advance these successes, we have assembled a multidisciplinary approach to understand, address, and resolve the role of pre-existing NAb to AAV capsid (over 80% of general population). A primary focus of PPG relates to molecular interactions between viral capsid in antibody response, engineering next generation vectors, and development and testing in novel NAb positive animal models. This PPG consists of 4 projects and 3 cores. Project 1 "FIX Gene Therapy and Role of AAV NAb" (PI - Dr. R. Jude Samulski) will capitalize on the availability of St. Jude FIX trial serum samples, humanized mouse models and peptide library to understand relationship between capsid antigen presentation and Ab response. Project 2 "Humanizing AAV Vectors for Gene Therapy" (PI- Dr. Aravind Asokan) will focus on engineering and utilizing novel AAV vectors in an effort to avoid NAb. Project 3 "Intra-articular AAV to Circumvent Systemic Neutralization" (PI - Dr. Paul Monahan) will utilize PPG gene transfer reagents to understand and prevent joint complications of hemophilia in animal models with pre-existing NAb. Project 4 "Generation of a Model of Hemophilia B and AAV Resistant Primates" (PIs Bruce Sullenger/Dougald Monroe): will use aptamer technology to generate and validate hemophilia in Ab+ non-human primate model for gene correction with PPG vectors, along with Administrative core (Pl-Dr. Samulski, Co-Dr. Monahan), vector and animal cores (Pls-Drs. Beecham & Li). This PPG is composed of unique group of researchers with expertise in biochemistry (Dr. Monroe), molecular biology (Dr. Sullenger), virology (Drs. Asokan & Samulski), and clinical hematology (Dr. Monahan) working synergistically to bring direct benefit of vector development (AAV), molecular therapeutics (sc-opt FIX and opt FVlll), and novel NAb non-human primate hemophilic model (aptamer) to bleeding disorders. The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery.

描述（由申请人提供）：“中和抗体 (NAb) 和 AAV FIX 基因治疗”计划项目拨款是一项及时的重点应用，其重点是推进令人兴奋的新临床数据，“自互补”(sc)AAV 因子 IX (FIX) 载体在临床研究中显示出有希望的成功 (5-8% > 1 年)。为了进一步推进这些成功，我们采用了一种多学科方法来理解、解决和解决现有 NAb 对 AAV 衣壳（超过 80% 的普通人群）的作用。 PPG 的主要关注点涉及抗体反应中病毒衣壳之间的分子相互作用、设计下一代载体以及新型 NAb 阳性动物模型的开发和测试。该PPG由4个项目和3个核心组成。项目 1“FIX 基因治疗和 AAV NAb 的作用”（PI - R. Jude Samulski 博士）将利用 St. Jude FIX 试验血清样本、人源化小鼠模型和肽库来了解衣壳抗原呈递和抗体反应之间的关系。项目 2“用于基因治疗的人性化 AAV 载体”（PI-Aravind Asokan 博士）将重点关注工程和利用新型 AAV 载体以避免 NAb。项目 3“关节内 AAV 规避全身中和”（PI - Paul Monahan 博士）将利用 PPG 基因转移试剂来了解和预防已存在 NAb 的动物模型中血友病的关节并发症。项目 4“B 型血友病和 AAV 抗性灵长类动物模型的生成”（PI Bruce Sullenger/Dougald Monroe）：将使用适体技术在 Ab+ 非人类灵长类动物模型中生成和验证血友病，以使用 PPG 载体以及管理核心（Pl-Dr. Samulski、Co-Dr. Monahan）、载体和动物核心（Pls-Drs. Beecham）进行基因校正＆李）。该 PPG 由具有生物化学（Monroe 博士）、分子生物学（Sullenger 博士）、病毒学（Asokan 和 Samulski 博士）和临床血液学（Monahan 博士）专业知识的独特研究人员组成，他们协同工作，为载体开发 (AAV)、分子疗法（sc-opt FIX 和 opt FVlll）以及新型 NAb 非人类带来直接益处出血性疾病的灵长类血友病模型（适体）。该 PPG 的长期目标是促进对载体-细胞-动物模型相互作用的基本理解，以实现安全的基因传递。