Adeno‐associated virus‐mediated gene transfer

Abstract

Although the remarkable versatility and efficacy of recombinant adeno-associated virus 2 (AAV2) vectors in transducing a wide variety of cells and tissues in vitro, and in numerous pre-clinical animal models of human diseases in vivo, have been well established, the published literature is replete with controversies with regard to the efficacy of AAV2 vectors in hematopoietic stem cell (HSC) transduction. A number of factors have contributed to these controversies, the molecular bases of which have begun to come to light in recent years. With the availability of several novel serotypes (AAV1 through AAV12), rational design of AAV capsid mutants, and strategies (selfcomplementary vector genomes, hematopoietic cell-specific promoters), it is indeed becoming feasible to achieve efficient transduction of HSC by AAV vectors in a murine serial bone marrow transplantation model in vivo, where stable integration of the proviral AAV genome does not lead to any overt hematological abnormalities. Thus, a better understanding of the AAV-HSC interactions, and the availability of a vast repertoire of novel serotype vectors, are likely to have significant implications in the use of AAV vectors in high-efficiency transduction of HSCs as well as in gene therapy applications involving the hematopoietic system. KeywordsAdeno-associated virus; Viral vectors; Gene transfer; Gene expression; Hematopoietic stem cells Gene therapy with vectors based on retroviruses and adenoviruses has been attempted in a number of clinical trials [Edelstein et al., 2007]. Initially, retroviral vectors yielded encouraging results, but the development of T cell lymphoma in non-human primates, and more recently, the development of T-cell leukemia in three children in a clinical trial for gene therapy of X-linked severe-combined immunodeficiency with these vectors has raised serious safety concerns [Deichmann et al., 2007;Hacein-Bey-Abina et al., 2003;Kohn et al., 2003]. Similarly, questions were raised with reference to efficacy of adenoviral vectors in gene therapy of cystic fibrosis, and subsequently, the death of a patient in a clinical trial for gene therapy of was attributed to the use of first-generation adenoviral vectors [Raper et al., 2003].A third group of viruses, termed parvoviruses, have to date not been associated with any malignant disease. In fact, parvoviruses have been shown to possess anti-tumor properties [Asokan and Samulski, 2005;Li et al., 2005]. Parvoviruses are among the smallest of known viruses, which contain a single-stranded DNA genome, and infect all vertebrates. One parvovirus of human origin, the adeno-associated virus 2 (AAV2), has been studied [Berns and Bohenzky, 1987;Muzyczka et al., 1984]. Although ∼90% of the human population is sero-positive for AAV2, no known disease has thus far been associated with AAV2 infection. AAV2 requires co-infection with a helper-virus, such as adenovirus, for its optimal replication, but in the absence of a helper-virus, the AAV2 genome integrates site-specifically into the huma...

The treatment of hemophilia A: from protein replacement to AAV-mediated gene therapy

“…In comparison with the prototypic AAV2, AAV vectors pseudotyped with other serotypes show superior transduction efficiency in various tissues: AAV1 in muscle, pancreatic islets, heart, vascular endothelium, brain, central nervous system (CNS) and liver; AAV3 in Cochlear inner hair cells; AAV4 in brain, lung, kidney, heart; AAV5 in brain and CNS, lung, eye, arthritic joints, and liver; AAV6 in heart, liver, skeletal muscle and airway epithelium; AAV7 in muscle, liver; AAV8 in muscle, pancreas, heart, and liver (Jiang et al 2006); AAV9 in heart, liver, CNS (Fechner et al 2008;Zincarelli et al 2008;Miyagi et al 2008;Klein et al 2008); AAV10 in CNS, hematopoietic stem cell (HSC), immune cells, skeletal muscle (Klein et al 2008;Maina et al 2008;Mori et al 2004Mori et al , 2008; AAV11 in immune cells, skeletal muscle (Mori et al 2004(Mori et al , 2008; AAV12 in HSC, muscle and salivary glands (Schmidt et al 2008;Srivastava 2008).…”

Targeted Gene Therapy for the Treatment of Heart Failure

“…83,90 The fact that they remain episomal eliminates the risk of insertional mutagenesis, although under rare circumstances it has been shown that the AAV genome can integrate. 91 A key advantage of rAAVs is that even though their genome remains episomal, they can still drive long-term expression. In several clinical trials, sustained transgene expression has been observed for 6 months to 3.7 years in patients 92–95 and up to 8 years in primates and canine models.…”

“…99,141 Recent studies, however, suggest the occurrence at low frequency of such integration events in tissues such as cardiac and skeletal muscle, 142 although the induction tumourigenesis has been disputed. 91,143–145 …”

A directed evolution approach to select for novel Adeno-associated virus capsids on an HIV-1 producer T cell line

“…These characteristics make AAV an appealing choice for gene transfer applications. Recombinant AAVs are being investigated as vectors for clinical gene transfer to a wide variety of cells and tissues (Hasbrouck and High, 2008; Kota et al, 2009; Maguire et al, 2009; Maguire et al, 2010; Muzyczka, 1992; Srivastava, 2008; Wagner et al, 1999). Transduction with AAV vectors has been shown to result in long-term transgene expression in vivo in several cell types including skeletal muscle, photoreceptors, liver, and neuronal cells (Daya and Berns, 2008; Hasbrouck and High, 2008; Liu et al, 2007).…”