Adeno-associated viral vectors for correction of inborn errors of metabolism: progressing towards clinical application.

Gene therapy holds great promise for the treatment of inherited metabolic disease. Among different vector systems used to date, vectors based on adeno-associated virus (AAV) have shown great potential for systemic expression of therapeutic transgenes. The main advantages of AAV are the beneficial safety profile and the possibility to generate long-term transgene expression without the necessity for chromosomal integration. Successful transduction of hepatocytes in the absence of immunological complications has been achieved in a number of animal species, including mice, dogs and nonhuman primates. Despite this plethora of successful studies, clinical applications have been lagging. Up to date, one clinical trial for liver-directed gene transfer has been performed and results underscored the important role of neutralizing antibodies towards the AAV capsid and the generation of cytotoxic T cell responses against transduced hepatocytes. Recently, a wide variation of novel AAV serotypes has emerged that shows great promise for improved gene transfer efficiency. However, one important factor hampering clinical progress has been the large degree of variability in terms of transduction efficiency and transgene expression levels of different AAV serotypes and the subsequent difficulties in the selection of a single serotype for clinical development. The aim of this review is to critically reevaluate pre-clinical data obtained in animal models of metabolic diseases in light of the progress that has been achieved in liver-directed gene transfer using AAV vectors. Using this evidence-based rationale, we have selected AAV8 as the serotype that combines the most favorable features for clinical applications of hepatic gene transfer.