Hematopoietic stem cell transduction by recombinant adeno-associated virus vectors: problems and solutions

Recombinant adeno-associated virus 2 (AAV) vectors have taken center stage owing to their potentially safer profile compared with the more commonly used retroviral and adenoviral vectors in human gene therapy clinical trials. Their remarkable versatility and efficacy in a wide variety of preclinical animal models of human diseases have attracted further attention of a number of investigators. Although two particular cell types, muscle and brain, have been shown to be highly transducible by AAV vectors, controversies abound with reference to the efficacy of these vectors in transducing primary hematopoietic cells. Whereas some investigators have claimed that primitive hematopoietic cells are impervious to AAV vectors, others have reported that AAV vectors are capable of transducing these cells, but only at high vector-to-cell ratios. Still other investigators have reported successful transduction of primitive hematopoietic cells at relatively low vector-to-cell ratios. This review attempts to resolve these controversies, and provides a basis for the optimism that safe and high-efficiency transduction of hematopoietic stem and progenitor cells by AAV vectors is well within reach.