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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Palmer, Donna J; Grove, Nathan C; Ing, Jordan et al. (2016) Homology Requirements for Efficient, Footprintless Gene Editing at the CFTR Locus in Human iPSCs with Helper-dependent Adenoviral Vectors. Mol Ther Nucleic Acids 5:e372
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
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
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
Brunetti-Pierri, N; Ng, Philip (2013) Adenoviral Vectors for Hemophilia Gene Therapy. J Genet Syndr Gene Ther 2:017
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
Guse, Kilian; Suzuki, Masataka; Sule, Gautam et al. (2012) Capsid-modified adenoviral vectors for improved muscle-directed gene therapy. Hum Gene Ther 23:1065-70
Brunetti-Pierri, Nicola; Liou, Aimee; Patel, Priti et al. (2012) Balloon catheter delivery of helper-dependent adenoviral vector results in sustained, therapeutic hFIX expression in rhesus macaques. Mol Ther 20:1863-70
Weaver, Eric A; Hillestad, Mathew L; Khare, Reeti et al. (2011) Characterization of species C human adenovirus serotype 6 (Ad6). Virology 412:19-27
Palmer, Donna J; Ng, Philip (2011) Rescue, amplification, and large-scale production of helper-dependent adenoviral vectors. Cold Spring Harb Protoc 2011:857-66

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