A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in canavan mice
Gene Therapy Center; Department of Microbiology and Physiological Systems; Department of Psychiatry; Department of Pediatrics
Genetic Processes | Immunoprophylaxis and Therapy | Molecular and Cellular Neuroscience | Molecular Genetics | Nervous System Diseases | Therapeutics
Canavan's disease (CD) is a fatal pediatric leukodystrophy caused by mutations in aspartoacylase (AspA) gene. Currently, there is no effective treatment for CD; however, gene therapy is an attractive approach to ameliorate the disease. Here, we studied progressive neuropathology and gene therapy in short-lived (≤ 1 month) AspA(-/-) mice, a bona-fide animal model for the severest form of CD. Single intravenous (IV) injections of several primate-derived recombinant adeno-associated viruses (rAAVs) as late as postnatal day 20 (P20) completely rescued their early lethality and alleviated the major disease symptoms, extending survival in P0-injected rAAV9 and rAAVrh8 groups to as long as 2 years thus far. We successfully used microRNA (miRNA)-mediated post-transcriptional detargeting for the first time to restrict therapeutic rAAV expression in the central nervous system (CNS) and minimize potentially deleterious effects of transgene overexpression in peripheral tissues. rAAV treatment globally improved CNS myelination, although some abnormalities persisted in the content and distribution of myelin-specific and -enriched lipids. We demonstrate that systemically delivered and CNS-restricted rAAVs can serve as efficacious and sustained gene therapeutics in a model of a severe neurodegenerative disorder even when administered as late as P20.
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Citation: Ahmed SS, Li H, Cao C, Sikoglu EM, Denninger AR, Su Q, Eaton S, Liso Navarro AA, Xie J, Szucs S, Zhang H, Moore C, Kirschner DA, Seyfried TN, Flotte TR, Matalon R, Gao G. A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in canavan mice. Mol Ther. 2013 Dec;21(12):2136-47. doi: 10.1038/mt.2013.138. Link to article on publisher's site
Ahmed, Seemin Seher; Li, Huapeng; Cao, Chunyan; Sikoglu, Elif M.; Denninger, Andrew R.; Su, Qin; Eaton, Samuel; Liso Navarro, Ana A.; Xie, Jun; Szucs, Sylvia; Zhang, Hongwei; Moore, Constance M.; Kirschner, Daniel A.; Seyfried, Thomas N.; Flotte, Terence R.; Matalon, Reuben; and Gao, Guangping, "A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in canavan mice" (2013). University of Massachusetts Medical School Faculty Publications. 359.