HDAd-mediated gene therapy for hemophilia B

Baylor College Of Medicine, Houston TX

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] HDAd are attractive gene therapy vectors that can mediate long-term, high level FIX expression from transduced hepatocytes leading to sustained phenotypic correction of FIX-deficiency in mice and dogs with no chronic toxicity. However, systemic high dose administration, required for efficient hepatic transduction, results in activation of an acute inflammatory response with potentially severe and lethal consequences. The mechanism responsible for Ad-mediated activation of the acute inflammatory response is not known, however, it is clearly dose-dependent. We have developed an in vivo gene therapy delivery approach for HDAd which has proven to be very successful in a large animal model. This method entails the use of balloon occlusion catheters to deliver HDAd preferentially to the liver of nonhuman primates. During the mentored phase, I propose to complete the nonhuman primate studies already initiated to establish dose-response relationship and vector biodistribution following vector delivery with this novel method. In Specific Aim 1, I will investigate the dose-response relationship ranging from 1x1010 to 1x1011 vp/kg of HDAd expressing baboon (-fetoprotein (bAFP) under the control of a liver specific promoter. In Specific Aim 2, I will investigate the biodistribution of HDAd vector delivered through balloon catheter-assisted delivery in nonhuman primates and to carry out formal toxicity studies, both performed under conditions to satisfy the requirements of the FDA for a phase I clinical trial. [unreadable] In the independent phase, I propose to investigate safety and efficacy of the balloon catheter-assisted delivery of HDAd into the clinically relevant animal model of hemophilia B. The proposed experiments are designed to generate the data necessary to progress towards human clinical trials for the treatment of hemophilia B (Specific Aim 3). In Specific Aim 4, I will investigate HDAd expressing genetically engineered FIX molecules with greater catalytic activity. This strategy is specifically designed to achieve therapeutic FIX levels using low vector doses. If superior, these catalytically enhanced FIX molecules will not only increase the safety and efficacy of HDAd-mediated hemophilia B gene therapy, but will also be valuable for other vector systems as well as for recombinant protein replacement therapy. During the independent phase I also propose to investigate, in nonhuman primates, the efficacy and safety of liver-directed gene therapy using naked plasmid DNA vector (pDNA) delivered through the balloon catheter-assisted delivery (Specific Aim 5). [unreadable] [unreadable]