AAV8-ApoE/AAT1-Null

Adeno-associated virus (AAV) is a small, single-stranded DNA virus that is nonpathogenic to human parvovirus and is an effective gene transfer vector for delivery of genes to different tissues, including the liver, without significant vector-related toxicity. Recombinant AAV (rAAV) has been clinically evaluated for in vivo gene therapy applications, including the treatment of hemophilia. rAAV serotype 2-mediated liver gene transfer for the treatment of hemophilia in humans resulted in a transient increase in liver enzymes and loss of transgene expression, followed by activation of a CD8+ T cell response against the AAV2 capsid. The magnitude of this adaptive immune response appears to be dose- and serotype-dependent, suggesting that highly liver-tropic and low-immunogenic AAV vectors may be required to achieve effective liver-directed gene therapy. Nonhuman primate-derived rAAV serotype 8 outperforms all other AAV serotypes in transducing hepatocytes in vivo and may be an ideal candidate for this purpose. Recently, in another hemophilia B gene therapy trial, combining an AAV8 capsid with a self-complementary vector genome to target the liver did result in adequate FIX transgene expression and improved bleeding phenotypes.