Recombinant adeno-associated virus vectors in the treatment of rare diseases

Abstract

Introduction An estimated 25 million Americans are living with rare diseases. Adeno-associated virus (AAV)-mediated gene therapy is an emerging therapeutic option for the more than 7,000 identified rare diseases. This paper highlights the benefits of AAV therapy compared to conventional small molecules, discusses current pre-clinical and clinical applications of AAV-mediated gene therapy, and offers insights into cutting edge research that will shape the future of AAV for broad therapeutic use. Areas covered In this review the biology of AAV and our ability to generate disease-specific variants is summarized. Limitations of current therapy are reviewed, with an emphasis on immune detection of virus, viral tropism and tissue targeting, and limitations of gene expression. Information for this review was found using PubMed and clinicaltrials.gov. Expert opinion Currently the scope of clinical trials of AAV gene therapy is concentrated in an array of phase I/II safety trials with less than two dozen rare diseases featured. Pre-clinical, translational studies are expanding in number as developments within the last decade have made generation of improved AAV vectors available to more researchers. Further, one bottleneck that is being overcome is the availability of disease models, which will allow for improved preclinical testing and advancement of AAV to more clinical applications.

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

“…A rapidly increasing number of publications have reported proof-of-concept for AAV-based gene therapy in animal models for various inherited liver disorders including urea cycle defects, organic acidurias, phenylketonuria, glycogen storage disease type Ia, long chain fatty acid oxidation disorders, homozygous familial hypercholesterolemia, primary hyperoxaluria type I and progressive familial intrahepatic cholestasis (Hastie and Samulski 2015 ; Junge et al 2015 ).…”

Systemic Safety of a Recombinant AAV8 Vector for Human Cocaine Hydrolase Gene Therapy: A Good Laboratory Practice Preclinical Study in Mice

“…Gene therapy using recombinant AAV is attractive because of efficient and prolonged transgene expression in target tissues. 20 AAV serotype 8 has shown a significantly greater liver transduction efficiently than those of other serotypes, which resulted in efforts to develop this virus as a gene therapy vector for hemophilia, 21 human immunodeficiency virus, 22 rare diseases, 23 and now cocaine Figure 6. Enzyme levels of CocH in plasma and tissues after AAV8-hCocH i.v.…”

Novel vectors and approaches for gene therapy in liver diseases

“…66 To produce recombinant AAV (rAAV) vectors, the rep and cap genes are removed from the viral genome and replaced with therapeutic sequence with only the ITRs maintained. 66,67 During the production process of rAAV, both rep and cap genes are provided in trans. The absence of rep results in the virus losing its ability to integrate, and once inside the nucleus the virus genome remains mostly episomal, which reduces the risk of insertional mutagenesis.…”