Helper-dependent adenoviral (HDAd) vectors are attractive gene therapy vectors tliat can mediate long-term, high level transgene expression from transduced hepatocytes resulting in sustained phenotypic correction of several small and large animal models 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 ofthe 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. In Specific Aim 1 we propose to perform studies needed to generate preclinical data to support a Phase 1/2 clinical trial using HDAd for hepatocyte gene therapy. From a risk:benefit perspective Crigler-Najjar syndrome type I, a severe inborn error of bilirubin metabolism, appears the best disease candidate. This disorder is also attractive because it requires low levels of transduction to achieve clinical benefit, and there are direct measures of clinical benefit available. The early results of that trial will have important implications for the hemophilia clinical trial which is intended to be the next disease candidate. In Specific Aim 2 we will investigate the safety and efficacy of balloon catheter-assisted delivery of HDAd into the hepatic artery of the clinically relevant hemophilia B dog model, and in Specific Aim 3 we will investigate this method in the rhesus macaque model. The absence of FIX inhibitor antibodies following the HDAd administration in both animal models will be an important safety consideration in the evaluation of this approach for clinical gene therapy. Specific Aim 4 is to investigate in nonhuman primates the efficacy and safety of liver-directed gene therapy using naked plasmid DNA vector (pDNA) encoding a reporter gene delivered through the balloon catheter-assisted delivery.
NIH ExPorter
NIH ExPorter