1081. Sustained Correction of Disease in Naïve and AAV2-Pretreated Hemophilia B Dogs Using Pseudotyped AAV Vectors

Abstract

Top of pageAbstract AAV7 and AAV8, new members of the AAV family isolated from non-human primate, are attractive candidates for hepatic gene transfer applications because of ten to hundred fold improved transduction efficiency in mouse liver models. Additionally, AAV7 and 8 has lesser frequency of pre-existing immunity in humans. These properties could solve some of the problems associated with AAV2 vectors. The benefits of AAV7 and 8 demonstrated in mouse models however have not been confirmed in larger animals. In this study, we evaluate the efficacy and safety of both AAV2/7 and 2/8 vectors in na|[iuml]|ve hemophilia B dogs, and also AAV2/8 in an AAV2-pretreated hemophilia B dog. Two na|[iuml]|ve hemophilia B dogs that received a single intraportal administration of 5.2x10e12 GC/kg of AAV2/8 vector have achieved sustained expression of 10% and 26% of normal levels of cFIX for over a year, while the na|[iuml]|ve dogs received AAV2/7 vectors at the same dose have generated 5% and 29% of normal levels of cFIX. In an AAV2-pretreated hemophilia B dog, cFIX expression increased from <1% to 16% of normal levels when treated with an AAV2/8 vector (9.28x10e12 GC/kg) and high level of expression has lasted for over two years. In all 5 treated dogs, clotting functions (WBCT and aPTT) have greatly improved and no bleeding episode has occurred since vector administration. No significant liver toxicity or cFIX-specific antibodies have been detected in AAV2/8-treated animals. However, one of the AAV2/7-treated dogs had elevated liver transaminase levels during the first 9 days after injection. Neutralizing antibody (NAB) response to AAV capsid was followed after vector injection. In the AAV2-preexposed dog, NAB to AAV2 was unexpected reactivated after AAV2/8 injection. These data provide the first safety and improved efficacy of AAV2/7 and 2/8 vector in large animal models for liver-directed gene therapy. Evaluation of AAV2/9 vector in hemophilia B dogs is currently under way and will be reported.