Neutralizing Antibody & AAV FIX Gene Therapy

描述（由申请人提供）：项目资助“中和抗体（NAb）和AAVFIX基因治疗”是一项及时的重点申请，重点关注推进令人兴奋的新临床数据，即“自互补”（SC）AAVFactor 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，我们已经组装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%的一般人群）。PPG的主要焦点涉及抗体应答中病毒衣壳之间的分子相互作用、工程化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）将利用St. Jude FIX试验血清样本、人源化小鼠模型和肽库的可用性，了解衣壳抗原呈递与Ab应答之间的关系。项目2“用于基因治疗的人源化AAV载体”（PI-Aravind Asokan博士）将专注于工程化和利用新型AAV载体以避免NAb。项目3“关节内AAV以避免全身中和”（PI -Paul Monahan博士）将利用PPG基因转移试剂了解和预防预先存在NAb的动物模型中血友病的关节并发症。项目4“血友病B和AAV耐药灵长类动物模型的生成”（PI布鲁斯Sulliver/Dougald门罗）：将使用适体技术生成并验证用于PPG载体基因校正的Ab+非人灵长类动物模型中的血友病，沿着管理核心（Pl-Dr. Samulski，Co-Dr. Monahan）、载体和动物核心（Pls-Drs. Beecham & Li）。该PPG由具有生物化学（门罗博士）、分子生物学（Sullivan博士）、病毒学（Asokan & 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，协同工作，为出血性疾病带来载体开发（AAV）、分子治疗（sc-opt FIX和opt FVIII）和新型NAb非人灵长类血友病模型（适体）的直接益处。该PPG的长期目标是推进对安全基因递送的载体-细胞-动物模型相互作用的基本理解。

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.