AAV DJ/8-Null

Recombinant adeno-associated virus (rAAV) vectors are used in clinical gene therapy because of their safety profile and clinical efficacy in phase I and II clinical trials. However, due in part to limited human trial experience, many fundamental factors of human gene therapy remain unresolved, such as determining whether the cause of immunity is due to transgene expression or AAV structural proteins. Most early AAV gene therapy studies were conducted with serotype 2 (AAV2) vectors because they exhibit broad tissue tropism and produce long-term transgene expression. In particular, AAV2 vectors can transduce human hepatocytes in vivo to produce therapeutic effects. Recently, however, vector systems based on other AAV serotypes are being investigated that have more efficient gene transduction and different cell and tissue specificities. One of the AAV serotypes, AAV serotype DJ/8 (AAV-DJ/8), has been reported to transduce hepatocytes and other cells and has been found to be superior to AAV2 in this function. AAV-DJ/8 was developed by rigorous screening of AAV variants on human hepatocytes using human anti-AAV antiserum. AAV-DJ/8 is a heparin-binding domain (HBD) mutant of AAV-DJ that is not only superior to all HBD-negative wild-type viruses (e.g., AAV8 and AAV9), but is also significantly superior to AAV2 in gene transduction into hepatocytes and other cells. The HBD is implicated in negative transduction in vivo (i.e., HBD deletion alleviates liver restriction and expands transduction into all non-liver tissues, including the brain), with the same transduction pattern as AAV8 and AAV9.