Obstacles to human hematopoietic stem cell transduction by recombinant adeno-associated virus 2 vectors.

Recombinant adeno-associated virus 2 (AAV) vectors have proven to be a potentially useful alternative to the more commonly used retroviral and adenoviral vectors for gene therapy in humans. Their safety and efficacy in Phase I clinical trials for gene therapy of cystic fibrosis and hemophilia B have been well documented, and their remarkable versatility and efficacy in a wide variety of pre-clinical models of human diseases have catapulted these vectors to the forefront. AAV vectors have been shown to be particularly well suited for transduction of brain and muscle cells. However, controversies exist with regard to their utility as a vector for gene transfer into human hematopoietic stem cells. On the one hand, some investigators have concluded that AAV vectors do not transduce hematopoietic stem cells at all, and others have reported that stem cell transduction requires enormously high vector-to-cell ratios. On the other hand, some investigators have reported high-efficiency transduction of human hematopoietic stem cells at low vector-to cell ratios. This article will provide a historical perspective as well as attempt to elaborate the reasons behind these controversies which have become clearer by studies focused on understanding, at the molecular level, the fundamental aspects of the life cycle of recombinant AAV vectors.