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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL073838-01A2
Application #
6869183
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Link, Rebecca P
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$375,000
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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Perrin, George Q; Zolotukhin, Irene; Sherman, Alexandra et al. (2016) Dynamics of antigen presentation to transgene product-specific CD4+ T cells and of Treg induction upon hepatic AAV gene transfer. Mol Ther Methods Clin Dev 3:16083
Patel, Nishil; Reiss, Ulrike; Davidoff, Andrew M et al. (2014) Progress towards gene therapy for haemophilia B. Int J Hematol 99:372-6
Nathwani, Amit C; Nienhuis, Arthur W; Davidoff, Andrew M (2014) Our journey to successful gene therapy for hemophilia B. Hum Gene Ther 25:923-6
Nathwani, Amit C; Reiss, Ulreke M; Tuddenham, Edward G D et al. (2014) Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 371:1994-2004
McIntosh, Jenny; Lenting, Peter J; Rosales, Cecilia et al. (2013) Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood 121:3335-44
Cancio, Maria I; Reiss, Ulrike M; Nathwani, Amit C et al. (2013) Developments in the treatment of hemophilia B: focus on emerging gene therapy. Appl Clin Genet 6:91-101
Sack, Brandon K; Merchant, Sherin; Markusic, David M et al. (2012) Transient B cell depletion or improved transgene expression by codon optimization promote tolerance to factor VIII in gene therapy. PLoS One 7:e37671
McIntosh, J H; Cochrane, M; Cobbold, S et al. (2012) Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine. Gene Ther 19:78-85
Fagone, Paolo; Wright, J Fraser; Nathwani, Amit C et al. (2012) Systemic errors in quantitative polymerase chain reaction titration of self-complementary adeno-associated viral vectors and improved alternative methods. Hum Gene Ther Methods 23:1-7

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