Hematopoietic Stem Cell Transduction by Recombinant Adeno-Associated Virus Vectors: Problems and Solutions

Abstract

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.

Adeno-associated virus type 5 exploits two different entry pathways in human embryo fibroblasts

“…AAV serotypes have been isolated from human and various non-human primate species and many have been developed to generate a variety of recombinant AAV (rAAV) vectors. The basic biology of AAV and its associated vectors is well-studied and clinical trials are now under investigation (for reviews, see Gao et al, 2005;Grieger et al, 2006;Grimm & Kay, 2003;Hendrie & Russell, 2005;Muzyczka & Warrington, 2005;Srivastava, 2005;Warrington & Herzog, 2006;Wu et al, 2006;Zhong et al, 2006). In gene therapy, targeting of viral vectors to the correct tissues and cells is essential.…”

Recombinant AAV2-mediated β-globin expression in human fetal hematopoietic cells from the aborted fetuses with β-thalassemia major

“…Therefore, it is necessary for further optimizing the experimental procedures by screening different serotypes of rAAVs (e.g. rAAV1, rAAV7 and rAAV8), using selfcomplementary double-stranded AAV vectors (scAAV), prolonging detection periods and enhancing hematopoietic cell survival to improve the efficiency of rAAV transduction and stably high expression of b-chains in vivo [34,35]. In summary, our data indicated that the rAAV2-b-globin could transduce fetal hematopoietic cells from b-thalassemia patients and mediate the stable expression of human b-globin in human hematopoietic cells in mice.…”

Down-regulation of expression of rat pyruvate dehydrogenase E1α gene by self-complementary adeno-associated virus-mediated small interfering RNA delivery

“…Recombinant AAV vectors have recently attracted increased attention for the purpose of gene therapy (Asokan et al, 2006;Flotte et al, 2005;Grieger et al, 2005;Srivastava et al, 2005). Studies have shown that AAV vectors based on serotype 2 (AAV2) can introduce a broad range of cell types, including non-dividing cells, in vitro and in vivo.…”