Title:The Adeno-associated Virus - A Safe and Promising Vehicle for Liverspecific Gene Therapy of Inherited and Non-inherited Disorders
VOLUME: 17 ISSUE: 1
Author(s):Kai Y. Mak, Indu G. Rajapaksha, Peter W. Angus and Chandana B. Herath*
Affiliation:Department of Medicine, the University of Melbourne, Austin Health, Heidelberg, Victoria, Department of Medicine, the University of Melbourne, Austin Health, Heidelberg, Victoria, Department of Gastroenterology and Hepatology, Austin Health, Heidelberg, Victoria, Department of Medicine, the University of Melbourne, Austin Health, Level 7, Lance Townsend Building, Austin Health, 145 Studley Road, Heidelberg, Victoria 3084
Keywords:Adeno-associated virus, angiotensin converting enzyme 2, gene therapy, liver, non-inherited disorders, renin angiotensin
system, viral vector.
Abstract:Introduction: The first human adeno-associated virus (AAV) was originally discovered in
1960s as a contaminant of adenovirus stock preparation and thus it had not been of medical interest.
Throughout the last three decades AAV has gained popularity to be used in gene therapy, mainly due
to its replicative defectiveness and lack of pathogenicity in human. In addition, its ability to mediate
stable and long-term expression in both non-dividing and dividing cells with specific tissue tropism
makes AAV one of the most promising candidates for therapeutic gene transfer to treat many inherited
as well as non-inherited disorders. Moreover, the use of AAV is not only restricted to overexpression
of recombinant transgene, but also to over-express short hairpin RNA and microRNA to
knockdown the expression of genes in targeted tissues.
Discussion and Conclusion: This review is organized into four parts. In the first part of the review,
we discuss about the discovery and history of AAV, followed by detailed AAV biology such as virus
genome, virus structure and its life cycle. In the second part of the review, the discussion is centred
on the molecular mechanisms of AAV and tissue transduction, including receptor recognition and
cell binding, endosomal entry, virus uncoating, nuclear entry and genome replication. Advantages
and limitations of using AAV as a safe vehicle for gene delivery is also discussed. In the third part of
the review, we discuss about the most commonly used AAV serotypes and variants isolated from
human and non-human primates, focusing on their diverse tissue tropisms, transduction efficiency,
immunological profiles and their applications in animal studies. Final part of the review focuses on
the recent progress of in-vivo gene transfer using AAV for inherited and non-inherited diseases in
both preclinical and clinical settings with a special emphasis on potential clinical applications of
AAV in the field of liver disease.
