Hemophilias A and B are due to mutations in the factor VIII and IX genes, respectively. These diseases are good models for gene therapy because of the relatively straightforward clinical parameters that include measurement of the transgene product by simple blood measurements and changes in clotting based on plasma levels. Patients with less than 1% clotting activity have very severe disease, between 1 to 5% a more moderate disease, and 5 to 20% mild disease. A wide-range of circulating factor is well tolerated making gene regulation unnecessary for gene therapy approaches. The liver is the organ in which these two clotting factors are normally synthesized. This makes it an attractive target for gene therapy approaches. While factor IX may be treatable with muscle delivery of a factor IX cDNA, factor VIII produced in the muscle is not efficiently secreted in the bloodstream. Moreover, there are still a number of issues that are unresolved when the muscle and liver approaches for treating FIX deficiency are directly compared. These include the relative risks of inhibitor formation, the ability to reach therapeutic versus curative levels of factor, and the relative dose of vector required to achieve a given level of plasma factor concentration. Recombinant AAV- mediated liver gene transfer has proven to be safe as well as efficacious in both small and large animal models of hemophilia. The goal of the proposal is to develop two phase I rAAV-mediated liver-based clinical trials for the treatment of hemophilias A and B. Our primary goal will be address the safety of this approach in humans. The secondary goal will be demonstrated phenotypic improvement in patients with hemophilia. The trial design here will also provide useful information for future liver- based clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL066948-01
Application #
6365588
Study Section
Special Emphasis Panel (ZHL1-CSR-C (S2))
Project Start
2000-09-28
Project End
2005-08-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
$248,650
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Margaritis, Paris (2010) Long-term expression of canine FVIIa in hemophilic dogs. Thromb Res 125 Suppl 1:S60-2
Margaritis, Paris; Roy, Elise; Aljamali, Majed N et al. (2009) Successful treatment of canine hemophilia by continuous expression of canine FVIIa. Blood 113:3682-9
Bedi, Maninder S; Alvarez Jr, Rene J; Kubota, Toru et al. (2008) Myocardial Fas and cytokine expression in end-stage heart failure: impact of LVAD support. Clin Transl Sci 1:245-8
Aljamali, Majed N; Margaritis, Paris; Schlachterman, Alexander et al. (2008) Long-term expression of murine activated factor VII is safe, but elevated levels cause premature mortality. J Clin Invest 118:1825-34
Akache, Bassel; Grimm, Dirk; Shen, Xuan et al. (2007) A two-hybrid screen identifies cathepsins B and L as uncoating factors for adeno-associated virus 2 and 8. Mol Ther 15:330-9
Chen, Jian; Wu, Qi; Yang, Pingar et al. (2006) Determination of specific CD4 and CD8 T cell epitopes after AAV2- and AAV8-hF.IX gene therapy. Mol Ther 13:260-9
Bedi, Maninder; McNamara, Dennis; London, Barry et al. (2006) Genetic susceptibility to atrial fibrillation in patients with congestive heart failure. Heart Rhythm 3:808-12
Grimm, Dirk; Pandey, Kusum; Nakai, Hiroyuki et al. (2006) Liver transduction with recombinant adeno-associated virus is primarily restricted by capsid serotype not vector genotype. J Virol 80:426-39
Inagaki, Katsuya; Fuess, Sally; Storm, Theresa A et al. (2006) Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Mol Ther 14:45-53
Manno, Catherine S; Arruda, Valder R; Pierce, Glenn F et al. (2006) Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 12:342-7

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