Clinical gene therapy using recombinant adeno-associated virus vectors

Abstract

Recombinant adeno-associated virus (rAAV) vectors possess a number of properties that may make them suitable for clinical gene therapy, including being based upon a virus for which there is no known pathology and a natural propensity to persist in human cells. Wild-type adeno-associated viruses (AAVs) are now known to be very diverse and ubiquitous in humans and nonhuman primates, which adds to the degree of confidence one may place in the natural history of AAV, namely that it has never been associated with any human tumors or other acute pathology, other than sporadic reports of having been isolated from spontaneously aborted fetuses. On the basis of this understanding of AAV biology and a wide range of preclinical studies in mice, rabbits, dogs and nonhuman primates, a growing number of clinical trials have been undertaken with this class of vectors. Altogether, over 40 clinical trials have now been approved. Although all previous trials were undertaken using AAV serotype 2 vectors, at least two current trials utilize AAV2 vector genomes cross-packaged or pseudotyped into AAV1 capsids, which appear to mediate more efficient gene delivery to muscle. The explosion of capsid isolates available for use as vectors to over 120 has now provided the potential to broaden the application of AAV-based gene therapy to other cell types.

Rapid, Simple, and Versatile Manufacturing of Recombinant Adeno-Associated Viral Vectors at Scale

“…T he use of recombinant adeno-associated viral (rAAV) vectors for clinical gene therapy applications has become widespread and is largely due to the demonstration of longterm transgene expression from rAAV vectors in animal models with little associated toxicity and good overall safety profiles in both preclinical and clinical trials Moss et al, 2004;Warrington and Herzog, 2006;Maguire et al, 2008;Mueller and Flotte, 2008;Brantly et al, 2009). Most early AAV gene therapy studies were performed with serotype 2 vectors, but vector systems based on other AAV serotypes with more efficient gene delivery and different tissue specificity are currently in human trials and their use will likely increase (Brantly et al, 2009;Neinhuis, 2009).…”

Persistence, Localization, and External Control of Transgene Expression After Single Injection of Adeno-Associated Virus into Injured Joints

“…AAV5 has recently been suggested to have better transduction efficiency in rodent arthritic joints. However, AAV2 has the best defined safety profile and it is used in clinical trials (Mueller and Flotte, 2008).…”

A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection

“…Gene therapy for muscular dystrophy and cardiomyopathy has been actively investigated as a promising and viable therapeutic approach (2). Gene vectors based on adeno-associated virus (AAV) are the most efficient vector systems currently available for gene delivery in the muscle and heart (3)(4)(5)(6)(7)(8). To realize significant benefits in muscular dystrophy patients, efficient systemic therapeutic gene delivery into striated muscles throughout the body is highly desirable.…”