Genotoxicity in Mice Following AAV Gene Delivery: A Safety Concern for Human Gene Therapy?

Randy J Chandler, Matthew C LaFave, Gaurav K Varshney, Shawn M Burgess and Charles P Venditti; (Nature) Molecular Therapy 24, 198-201 (February 2016) | doi:10.1038/mt.2016.17


Given the lack of therapies for the many diseases that rAAV gene therapy promises to treat, such as lethal inborn errors of metabolism, the risk of toxicity imposed by rAAV exposure will need to be balanced against the significant benefits offered by effective gene therapy, which for some patients could be lifesaving.

Although the lack of natural pathogenicity and the capacity for effective gene delivery coupled with stable, long-term gene expression have supported the advancement of rAAV as an optimal vector for human clinical trials, recent studies in mice have challenged the belief that rAAV is an innocuous gene therapy vector.

MicroRNAs Form Triplexes with Double Stranded DNA at Sequence-Specific Binding Sites; a Eukaryotic Mechanism via which microRNAs Could Directly Alter Gene Expression

Paugh SW, Coss DR, Bao J, Laudermilk LT, Grace CR, Ferreira AM, M. Brett Waddell, Granger Ridout, Deanna Naeve, Michael Leuze, Philip F. LoCascio, John C. Panetta, Mark R. Wilkinson, Ching-Hon Pui, Clayton W. Naeve, Edward C. Uberbacher, Erik J. Bonten, William E. Evans (2016); PLoS Comput Biol 12(2): e1004744. doi:10.1371/journal.pcbi.1004744

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Friedreichs ataxia, the most common form of ataxia in humans, is caused by the expansion of a (GAA)n repeat in intron 1 of the Frataxin gene, which in turn results in transcriptional silencing, presumably because of the triplex-forming potential of the (GAA)n repeat. This suggests that, not only may the formation of DNA triplexes be a well-conserved and essential mechanism to regulate gene transcription, but that stable or prolonged triplex formation may have undesirable consequences.