Helper-dependent adenoviruses (HDAd) can transduce hepatocytes to direct high level, long-term transgene expression with no chronic toxicity. However, high doses are required for efficient transduction following systemic administration which results in an acute inflammatory response which can lead to severe and lethal acute toxicity. This is the most significant obstacle hindering clinical progress of this otherwise promising technology. The severity of this response appears to be 1) clearly dose-dependent and 2) related to systemic vector dissemination. Therefore, we hypothesize that this acute toxicity can be minimized/eliminated by delivering the vector exclusively/preferentially to the liver to permit high efficiency hepatic transduction with very low doses and with no/minimal systemic vector dissemination.
Specific Aim 1 is to ascertain whether there is a direct correlation between hepatic transduction and the severity of acute toxicity in mice. This is important because it directly relates to the clinical reality of liver-directed gene therapy using HDAd. Our preliminary results suggest that systemic vector dissemination, rather than hepatic transduction plays a major role in acute inflammatory response activation.
Specific Aim 2 is to investigate the safety, feasibility and efficacy of delivering HDAd exclusively into the liver by developing minimally invasive, clinically relevant, percutaneous approaches to achieve liver exclusive vector delivery in baboons using balloon occlusion catheters. Our preliminary results in mice and baboons suggest that liver exclusive vector delivery will permit efficient hepatic transduction with low doses thus minimizing systemic dissemination and acute toxicity.
Specific Aim 3 is to investigate the long term effects of liver exclusive vector delivery in baboons, such as duration of transgene expression, chronic toxicity and readministration.
Specific Aim 4 is to develop a method of mimicking hydrodynamic injection of HDAd in baboons that is noninvasive and does not require large injection volumes. Our preliminary results in a baboon suggest that this novel delivery method has the potential of dramatically increasing the vector's therapeutic index by permitting exceedingly high, unprecedented levels of hepatic transduction with low vector doses and with reduced systemic vector dissemination and proinflammatory cytokines. Successful completion of these studies may finally permit safe and efficacious HDAd-mediated, liver-directed gene therapy for a wide variety of genetic diseases.
|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|
Showing the most recent 10 out of 27 publications