Gene therapy progress and prospects: recombinant adeno-associated virus (rAAV) vectors.

Abstract

Recombinant adeno-associated virus (rAAV) vectors areunique among the vector classes currently available forhuman gene therapy in that they are based upon a classof viruses that commonly inhabits a human host withoutcausing any detectable pathology. This fact, combinedwith the propensity of AAV to establish long-termpersistence in human cells, could lead one to hypothesizethat this class of vectors would be ideal for a varietyof gene therapy approaches. However, a number ofsignificant limitations to the utility of this system haverecently been identified, including the paucity of cellsurface receptors on some cells for the most common AAVserotype, AAV2, the loss of site-specific integration byrecombinant AAV vectors, and the presence of hostimmune responses to AAV capsid components andtransgene products. Driven by these limitations, newgenerations of rAAV vectors have recently emerged, basedon a number of alternative AAV serotypes or on designermutants of the AAV capsid, which have been retargeted forentry into previously nonpermissive cells. Finally, a deeperunderstanding of the mechanisms of AAV integration andpersistence promise to make it possible to recapture thebest features of the native virus and allow this system tomove forward into broader clinical application.