rAAV-Mediated Gene Therapy for Hemophillia B

rAAV 介导的 B 型血友病基因治疗

• 批准号: 6869183
• 负责人: ANDREW M DAVIDOFF
• 金额: $ 37.5万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869183
• 关键词: Macaca mulatta; adeno associated virus group; androgens; biotechnology; clinical research; gene delivery system; gene therapy; hemophilia B; human tissue; immunosuppressive; laboratory mouse; liver; nonhuman therapy evaluation; recombinant virus; transfection /expression vector

DESCRIPTION (provided by applicant): Hemophilia B is an inherited bleeding disorder that is due to a defect in blood coagulation factor IX (FIX) synthesis. A gene therapy mediated approach to the replacement of FIX has a number of advantages, particularly the potential for sustained expression. The overriding hypothesis to be tested in this project is that liver-targeted delivery of recombinant adeno-associated virus (rAAV) vectors encoding the cDNA for human factor IX (hFIX) can safely mediate long-term expression of therapeutic levels of hFIX. This approach has been used successfully to generate normal levels of hFIX in mice but has not yet consistently been successful in a relevant nonhuman primate model or in humans. Optimal delivery methods need to be established to ensure efficient rAAV transduction of the primate liver with persistent, high-level transgene expression, and with minimal procedure or vector-related toxicity. In addition, the impact of naturally acquired and iatrogenic immunity to AAV on transduction efficiency with rAAV vectors and the ability to manipulate these potential immunologic obstacles to successful gene transfer is unknown. Finally, demonstrating the safety of this gene therapy mediated approach is of critical importance prior to initiating a clinical trial. This proposed study is designed to address these critical issues in a context that is relevant to humans. The following hypotheses will be tested: (1) rAAV particles of an alternative serotype, rAAV-8, can generate systemic levels of hFIX that are greater than those obtained by rAAV-5 particles, and equivalent transduction efficiency can be achieved whether using the mesenteric or peripheral venous route of vector administration. (2) Equivalent transduction efficiency can be achieved with vector re-administration either when an alternate rAAV serotype is used or when transient immunosuppression is utilized at the time of initial vector administration. (3) rAAV mediated transfer targeting the liver is safe, will not lead to germ line transmission, and will be free of long term toxicity, including organ damage, and the development of malignancy. Data generated from these studies will provide insight and preclinical data for a gene therapy trial not only for hemophilia B, but also for other potential trials in which AAV-mediated liver-targeted gene therapy might be employed.

描述(申请人提供)：血友病B是一种遗传性出血性疾病，是由于凝血因子IX(FIX)合成缺陷引起的。基因治疗介导的FIX替代方法有许多优点，特别是具有持续表达的潜力。在这个项目中要检验的最重要的假设是，肝脏靶向递送编码人凝血因子IX(HFIX)的重组腺相关病毒(RAAV)载体可以安全地介导hFIX治疗水平的长期表达。这种方法已经成功地在小鼠身上产生了正常水平的hFIX，但在相关的非人类灵长类动物模型或人类中还没有始终如一地成功。需要建立最佳的递送方法，以确保高效的rAAV转导灵长类动物肝脏，具有持续、高水平的转基因表达，并具有最小的程序或与载体相关的毒性。此外，对AAV的自然获得性和医源性免疫对rAAV载体转导效率的影响以及操纵这些潜在的免疫障碍成功进行基因转移的能力尚不清楚。最后，在启动临床试验之前，证明这种基因治疗方法的安全性是至关重要的。这项拟议的研究旨在与人类相关的背景下解决这些关键问题。将检验以下假设：(1)另一种血清型rAAV-8的rAAV颗粒可以产生比rAAV-5颗粒更高的hFIX水平，并且无论是使用肠系膜途径还是外周静脉途径给药，都可以获得同等的转导效率。(2)无论是使用另一种rAAV血清型，还是在初始给药时使用一过性免疫抑制，重新给药均可获得相同的转导效率。(3)rAAV介导的肝靶向转移是安全的，不会导致生殖系传播，并且没有包括器官损伤和恶性发展在内的长期毒性。这些研究产生的数据不仅将为血友病B的基因治疗试验提供洞察力和临床前数据，还将为可能采用AAV介导的肝脏靶向基因治疗的其他潜在试验提供洞察力和临床前数据。