? 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 hemophilia B subjects was initiated 4 years ago. Overall the vector delivery through the hepatic artery was well tolerated 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 DMA synthesis we will determine if MMF/TC will interfere with gene transfer/transgene expression, duration of the vector capsid persistence, in the 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 hemophilia 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. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084220-02
Application #
7246535
Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
Program Officer
Link, Rebecca P
Project Start
2006-06-13
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$362,364
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Finn, Jonathan D; Ozelo, Margareth C; Sabatino, Denise E et al. (2010) Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. Blood 116:5842-8
Favaro, Patricia; Downey, Harre D; Zhou, J Shangzhen et al. (2009) Host and vector-dependent effects on the risk of germline transmission of AAV vectors. Mol Ther 17:1022-30
Sabatino, Denise E; Freguia, Christian Furlan; Toso, Raffaella et al. (2009) Recombinant canine B-domain-deleted FVIII exhibits high specific activity and is safe in the canine hemophilia A model. Blood 114:4562-5
Arruda, Valder R; Favaro, Patricia; Finn, Jonathan D (2009) Strategies to modulate immune responses: a new frontier for gene therapy. Mol Ther 17:1492-503
Mingozzi, Federico; Hasbrouck, Nicole C; Basner-Tschakarjan, Etiena et al. (2007) Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood 110:2334-41