Transient expression of factor VIII and a chronic high-fat diet induces ER stress and late hepatocyte oncogenesis

Abstract

Liver-directed gene therapy using adeno-associated virus (AAV) for delivery of therapeutic transgenes has posed particular challenges over the past 25 years, and there are no FDA-approved products to date. Reasons include lack of efficacy or toxicity or both, despite acceptable efficacy and toxicology results in animals, including non-human primates. The experience with AAV-mediated gene therapy for hemophilia is a case in point. The clotting factor VIII gene was cloned in 1984, but production of the full-length recombinant protein is challenging.