rAAV-Mediated Gene Therapy for Hemophillia B

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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.