Basic Biology of Adeno-Associated Virus (AAV) Vectors Used in Gene Therapy

Abstract

Adeno-associated virus (AAV) based vectors have emerged as important tools for gene therapy in humans. The recent successes seen in Phase I/II clinical trials have also highlighted the issues related to the host and vector-related immune response that preclude the universal application of this promising vector system. A fundamental insight into the biological mechanisms by which AAV infects the host cell and a thorough understanding of the immediate and long-lived cellular responses to AAV infection is likely to offer clues and help design better intervention strategies to improve the therapeutic efficiency of AAV vectors. This article reviews the biology of AAV-host cellular interactions and outlines their application in the development of novel and improved AAV vector systems.

Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9

“…b) The results were obtained by bioluminescence imaging following AAV systemic injection in male adult mice. Adapted from: [1,15], [19,20] Abbreviations: NHP -Non-human primates; ? -Unknown; HGFR -hepatocyte growth factor receptor; LamR -Laminin Receptor; FGFR1 -fibroblast growth factor receptor 1; HSPG -Heparan sulfate proteoglycan; EGFR -epidermal growth factor receptor; PDGFR -platelet-derived growth factor receptor; NAbs -neutralizing antibodies; SM-skeletal muscle; HCC-hepatocellular carcinoma; IV-intravenous; -: no transduction; + : low levels; ++ : moderate levels; +++ : high levels; A : anterograde transport; R : Retrograde transport.…”

“…Successful transduction by AAV vectors starts with cell surface receptor binding and depends on several subsequent steps, such as endocytic uptake, escape from the endosomal pathway, entry into the cell nucleus, virus uncoating and single-stranded genome release, second-strand synthesis and finally transcription [1,15]. After cell infection, the virus might follow two different life cycle pathways.…”

“…However, in the lack of helper viruses, AAV enters in a latent stage, in which the genome can either persist in an extrachromosomal state or integrate into the host cell genome [15]. This integration event happens in a specific site in the q arm of human chromosome 19 (AAVS1), in a process that depends on AAV ITRs and Rep proteins [21].…”

Gene therapy and the adeno‐associated virus in the treatment of genetic and acquired ophthalmic diseases in humans: Trials, future directions and safety considerations

“…AAV is a member of the Parvoviridae family of single‐stranded DNA viruses. It is approximately 20 nm in diameter with its natural genome consisting of approximately 4.8 kilobases (kb) of DNA consisting of Rep and Cap genes, flanked by two inverted terminal repeats (ITRs) at the termini . The Rep gene encodes proteins (Rep78, Rep68, Rep52 and Rep40) required for viral replication and packaging.…”

Precision Fluorescent Labeling of an Adeno‐Associated Virus Vector to Monitor the Viral Infection Pathway

“…Development of AAV as a delivery vector has attracted attention in the past decade owing to its high safety profile and persistent transgene expression . To obtain successful transduction of AAV, viral vectors carrying therapeutic genes must overcome barriers, such as preexisting neutralizing antibodies and proteolytic enzymes in the blood and various cellular components of the host cell, and enter host cell nuclei, where therapeutic genes can be expressed . At present, most studies on AAV infections have concentrated on the proteins involved in AAV DNA replication and the transcription factors that bind to the AAV promoter .…”