397. AAV-Mediated Gene Transfer to Endothelial Cells

Abstract

Adeno-associated virus (AAV) vectors have been evaluated in clinical studies of gene transfer for hemophilia by two different strategies, one using liver as the target tissue and the other using skeletal muscle. Both routes have resulted in long-term cures in hemophilic dogs. In humans, delivery to skeletal muscle resulted in long-term expression but at sub-therapeutic levels, while the liver-targeted study raised expression to therapeutic levels at the highest dose, although duration of expression was only short-lived (<10 weeks). Moreover, the high prevalence of hepatitis in the adult hemophilia population limits the utility of liver as a target tissue in practice. Therefore we investigated the possibility of targeting other cell types. Endothelial cells (ECs) are of interest because of their easy accessibility and the direct secretion of transgene product into the circulation.