Neutralizing Antibody & AAV FIX Gene Therapy

描述(由申请人提供)：计划项目拨款“中和抗体(NAB)和AAV修复基因疗法”是一个及时集中的应用，以推进令人兴奋的新临床数据为中心，“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%；1年)。为了进一步推动这些成功，我们集合了一个多学科的方法来理解、解决和解决先前存在的NAB到AAV衣壳(超过80%的一般人口)的作用。PPG的一个主要焦点涉及抗体应答中病毒衣壳之间的分子相互作用，工程下一代载体，以及在新的NAB阳性动物模型中的开发和测试。这个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-Dr.R.Jude Samulski)将利用St.Jude FIX试验血清样本、人源化小鼠模型和多肽库来了解衣壳抗原呈递和抗体应答之间的关系。项目2“人源化AAV载体用于基因治疗”(Pi-Dr.Aravind Asokan)将专注于设计和利用新的AAV载体，以努力避免NAB。项目3“关节内AAV避免全身中和”(Pi-Paul Monahan博士)将利用PPG基因转移试剂来了解和预防血友病动物模型中既有NAB的关节并发症。项目4“血友病B和抗甲型肝炎病毒灵长类动物模型的建立”(Pis Bruce Sulenger/Dougald Monroe)：将使用适体技术在抗体+非人类灵长类动物模型中生成和验证血友病，以利用PPG载体和管理核心(Pl-DR)进行基因校正。萨穆尔斯基，共同博士。Monahan)、载体和动物核心(请参见Beecham&Li)。PPG由一组独特的研究人员组成，他们在生物化学(Monroe博士)、分子生物学(Sullener博士)、病毒学(Asokan&Samulski博士)和临床血液学(Monahan博士)方面具有专长，协同工作可为出血性疾病带来载体开发(AAV)、分子疗法(sc-opt fix和opt FVlll)和新型NAB非人灵长类血友病模型(ApTamer)的直接好处。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。

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.