Hemophilia B is a inherited bleeding disorder characterized by a deficiency of factor IX (F.IX). The disease is an excellent candidate for treatment by gene-based therapy because F.IX as low as 1-5% of normal is associated with clinical benefits. A Phase l/ll clinical study on IAAV-2, liver-directed F.IX gene transfer to lemophilia B subjects was initiated 4 years ago. Overall the vector delivery through the hepatic artery was well derated with no serious adverse event. One subject in the high dose group had circulating F. IX levels of 12% of normal 2 weeks after receiving vector, but expression was short lived. The loss of expression was accompanied by an asymptomatic transaminitis that resolved spontaneously. There is high likelihood that immune-mediated destruction of the transduced hepatocytes was responsible for transaminitis and loss of expression. To circumvent this occurrence, we will test whether immunomodulation allows expression without hepatocyte damage. The overall goal of this work is to establish the efficacy and safety of a transient immunosuppressive regimen with mycophenolate mofetil (MMF) and tacrolimus (TC) on AAV-2-F.IX. The regimen consisting of MMF/TC has been extensively tested for long-term immune-suppressive therapy in organ transplant recipients and subjects with autoimmune diseases.
In aim 1 we will use non-human primates (NHP), the closest model to human to establish the efficacy and safety of MMF/TC regimen on AAV-2-liver-directed gene transfer. Because these drugs may interfere with double strand DNA synthesis we will determine f MMF/TC will interfere with gene transfer/transgene expression, duration of the vector capsid persistence, in he liver tissue and with vector biodistribution by injecting AAV-2 in NHP. The results will provide the basis for a new dose escalation Phase l/ll clinical study on AAV-2-mediated, liver-direct F.IX gene delivery to adult nemophilia B subjects (aims 2-4). Our main goal is to determine the safety of this approach by monitoring subjects for local and systemic toxicity, vector biodistribution, and for antibody formation to F.IX. Specifically, we will characterize the role of neutralizing antibody to AAV-2 capsid on preventing AAV-2 transduction, will define the immune responses to AAV capsid peptides and determine the duration of the immunomodulation required. We also plan to evaluate the potential efficacy in each subject by measuring biological activity of F. IX. Both preclinical and clinical experiments proposed here will provide useful information not only for the AAV-2 mediated gene transfer but also for experiments proposed in Project 5 of this PEGT.
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