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. 2017 Apr;28(4):314-322.
doi: 10.1089/hum.2017.009.

Recombinant Adeno-Associated Viral Integration and Genotoxicity: Insights from Animal Models

Randy J Chandler  1 , Mark S Sands  2   3 , Charles P Venditti  1
Affiliations

Recombinant Adeno-Associated Viral Integration and Genotoxicity: Insights from Animal Models

Randy J Chandler et al. Hum Gene Ther. 2017 Apr.

Abstract

Currently, clinical gene therapy is experiencing a renaissance, with new products for clinical use approved in Europe and clinical trials for multiple diseases reporting positive results, especially those using recombinant adeno-associated viral (rAAV) vectors. Amid this new success, it is prudent to recall that the field of gene therapy experienced tragic setbacks in 1999 and 2002 because of the serious adverse events related to retroviral and adenoviral gene delivery in two clinical trials that resulted in the death of two patients. In both cases, the toxicity observed in humans had been documented to occur in animal models. However, these toxicities were either undetected or underappreciated before they arose in humans. rAAVs have been tested extensively in animals and animal models of disease, largely without adverse events, except for transient elevation in liver enzymes in some patients. However, a small but growing number of murine studies have documented that adeno-associated viral gene delivery can result in insertional mutagenesis. Herein, the aggregate data are reviewed from multiple murine studies where genotoxicity associated with rAAV treatment has been observed. The data emphasize the need for a proactive position to evaluate the potential risks and possible solutions associated with AAV-mediated gene therapy.

Keywords: AAV; HCC; cancer; gene therapy; genotoxicity; insertional mutagenesis.

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Conflict of interest statement

No competing financial interests exist.

Figures

<b>Figure 1.</b>
Figure 1.
(A) A genomic alignment showing an alignment of 31 syntenic vertebrate sequences around the miR341 locus of the mouse, and the position of a small simple repeat within the gene. (B) A base pair resolution map shows the CGGT repeat with mapped AAV integrations indicated as colored dots, with the corresponding study. The relative conservation of each base was measured and depicted with a logo plot where the height is proportional to conservation and boldness indicates more sequences.
<b>Figure 1.</b>
Figure 1.
(A) A genomic alignment showing an alignment of 31 syntenic vertebrate sequences around the miR341 locus of the mouse, and the position of a small simple repeat within the gene. (B) A base pair resolution map shows the CGGT repeat with mapped AAV integrations indicated as colored dots, with the corresponding study. The relative conservation of each base was measured and depicted with a logo plot where the height is proportional to conservation and boldness indicates more sequences.
See this image and copyright information in PMC

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