We have developed a balloon occlusion catheter method of delivering helper-dependent adenoviral vectors preferentially into the liver of nonhuman primates. This method results in high efficiency hepatocyte transduction and high level, long-term transgene expression with minimal toxicity. In this application, we propose to address the few outstanding issues before potential clinical application of this technology.
Specific Aim 1 is to eliminate the hypotension that is associated with our balloon occlusion method of vector delivery thereby enhancing safety.
Specific Aim 2 is to determine the % hepatoctye transduction achievable with various vector doses delivered by our balloon occlusion method to permit better assessment of risk:benefit.
Specific Aim 3 is to determine the safety and efficacy of delivering a helper-dependent adenoviral vector expressing canine coagulation factor IX by the balloon method into FIX-deficient dogs as a model for hemophilia B gene therapy.

Public Health Relevance

Gene therapy has the potential to cure genetic and acquired diseases. This application proposes to refine and test a novel method of performing gene therapy. We will also evaluate our unique gene therapy technique in a dog model of a human bleeding disorder.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases (TAG)
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Doo, Edward
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Baylor College of Medicine
Schools of Medicine
United States
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Weaver, Eric A; Nehete, Pramod N; Nehete, Bharti P et al. (2013) Comparison of systemic and mucosal immunization with helper-dependent adenoviruses for vaccination against mucosal challenge with SHIV. PLoS One 8:e67574
Suzuki, Masataka; Bertin, Terry K; Rogers, Geoffrey L et al. (2013) Differential type I interferon-dependent transgene silencing of helper-dependent adenoviral vs. adeno-associated viral vectors in vivo. Mol Ther 21:796-805
Piccolo, Pasquale; Vetrini, Francesco; Mithbaokar, Pratibha et al. (2013) SR-A and SREC-I are Kupffer and endothelial cell receptors for helper-dependent adenoviral vectors. Mol Ther 21:767-74
Brunetti-Pierri, Nicola; Ng, Thomas; Iannitti, David et al. (2013) Transgene expression up to 7 years in nonhuman primates following hepatic transduction with helper-dependent adenoviral vectors. Hum Gene Ther 24:761-5
Weaver, Eric A; Hillestad, Mathew L; Khare, Reeti et al. (2011) Characterization of species C human adenovirus serotype 6 (Ad6). Virology 412:19-27
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Palmer, Donna J; Ng, Philip (2011) Characterization of helper-dependent adenoviral vectors. Cold Spring Harb Protoc 2011:867-70
Dimmock, David; Brunetti-Pierri, Nicola; Palmer, Donna J et al. (2011) Correction of hyperbilirubinemia in gunn rats using clinically relevant low doses of helper-dependent adenoviral vectors. Hum Gene Ther 22:483-8
Prill, Jan-Michael; Espenlaub, Sigrid; Samen, Ulrike et al. (2011) Modifications of adenovirus hexon allow for either hepatocyte detargeting or targeting with potential evasion from Kupffer cells. Mol Ther 19:83-92
Khare, Reeti; May, Shannon M; Vetrini, Francesco et al. (2011) Generation of a Kupffer cell-evading adenovirus for systemic and liver-directed gene transfer. Mol Ther 19:1254-62

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