Long-Term Follow-Up of the First In Human Intravascular Delivery of AAV For Gene Transfer: AAV2-hFIX16 For Severe Hemophilia B

Abstract Adeno-associated viral (AAV) vectors are a leading platform for gene based therapies for both monogenic and complex acquired disorders. The success of AAV gene transfer highlights the need to answer outstanding clinical questions of safety, durability and the nature of the human immune response to AAV vectors. Here we present longitudinal follow up data of subjects who participated in the first trial of a systemically-delivered AAV vector. Adult males (n=7) with severe hemophilia B received an AAV2 vector at doses ranging from 8x1010 - 2x1012 vg/kg to target hepatocyte-specific expression of coagulation factor IX; a subset (n=4) were followed for 12-15 years post vector administration. No major safety concerns were observed. There was no evidence of sustained hepatic toxicity or development of hepatocellular carcinoma as assessed by liver transaminase values, serum α-fetoprotein and liver ultrasound. Subjects demonstrated persistant, increased AAV neutralizing antibodies (NAb) to the infused AAV serotype (AAV2) as well as all other AAV serotypes tested (AAV5 and AAV8) for the duration of follow up. These data represent the longest available longitudinal follow up data of subjects who received intravascular AAV and support the preliminary safety of intravascular AAV administration at the doses tested in adults. Data demonstrate, for the first time, the persistence of high-titer, multi-serotype cross-reactive AAV NAb for up to 15 years post AAV vector administration. Our observations are broadly applicable to the development of AAV-mediated gene therapy.