Neutralizing Antibody & AAV FIX Gene Therapy

项目描述（由申请人提供）：“中和抗体（NAb）和AAV FIX基因治疗”是一项及时的重点申请，旨在推进令人兴奋的新临床数据，即“自我互补”（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%）。为了进一步推进这些成功，我们集合了一个多学科的方法来理解、处理和解决预先存在的NAb对AAV衣壳的作用（超过80%的普通人群）。PPG的一个主要焦点涉及抗体反应中病毒衣壳之间的分子相互作用，下一代载体的工程设计以及新型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。

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.