Neutralizing Antibody & AAV FIX Gene Therapy

中和抗体

基本信息

批准号：
8616782
负责人：
RICHARD J SAMULSKI
金额：
$ 227.82万
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/8616782
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）：计划项目赠款“中和抗体（NAB）和AAV固定基因疗法”是一种及时集中的应用程序，围绕着促进令人兴奋的新临床数据，即“自我补充”（SC）AAV因子IX（FIX）载体（FIX）载体显示出在临床研究中有希望的成功（5-8％> 1yR）。为了进一步促进这些成功，我们汇集了一种多学科的方法，以理解，解决和解决先前存在的NAB对AAV CAPSID（超过80％的一般人群）的作用。 PPG的主要重点涉及抗体反应中的病毒capsid之间的分子相互作用，工程下一代载体以及新型NAB阳性动物模型中的开发和测试。该PPG由4个项目和3个核心组成。项目1“修复基因疗法和AAV NAB的作用”（PI -R。Jude Samulski博士）将利用St. Jude Fix Fix试验的可用性，人源化小鼠模型和肽文库，以了解帽壳抗原表现和AB反应之间的关系。项目2“基因治疗的AAV载体人性化”（Pi-Aravind Asokan博士）将着重于工程和利用新型的AAV矢量，以避免使用NAB。项目3“关节内AAV规避系统性中和”（PI-Paul Monahan博士）将利用PPG基因转移试剂来理解和防止具有预先存在NAB的动物模型中血友病的关节并发症。项目4“生成B和AAV抗性灵长类动物的模型”（Pis 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与PPG矢量校正基因的非人类灵长类动物模型，以及行政核心（Pls Dr.Samuls coers coers co-drs co-drs and co-dr。＆li）。该PPG由具有生物化学专业知识的独特研究人员组成（Monroe博士），分子生物学（Sullenger博士），病毒学博士学位，病毒学（Asokan＆Samulski博士）和临床血液学（Monahan博士（Monahan）（Monahan博士）协同工作，以实现直接的效果，以实现分子发展（AAV）的直接益处（AAV），NOMELECULL FIXER（AAV），FIX和FVALL FIXL和FIXLL FIXL和FIXLL FIXL和FIXER FIXL和FIXER FIXEB FIXER和FIXER FIXL和FIXER FIXEB FIXEB FIXIB和FIXIB FIXER FIXER（AAV）进行。灵长类动物的血友病模型（适体）流血疾病。该PPG的长期目标是提高对矢量细胞 - 动物模型相互作用的基本了解，以实现安全基因递送。