A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS gene therapy in Canavan mice

Seemin Seher Ahmed, Huapeng Li, Chunyan Cao, Elif M. Sikoglu, Andrew R. Denninger, Qin Su, Samuel Eaton, Ana A. Liso Navarro, Jun Xie, Sylvia Szucs, Hongwei Zhang, Constance Moore, Daniel A. Kirschner, Thomas N. Seyfried, Terence R. Flotte, Reuben Matalon, Guangping Gao

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2136-2147
Number of pages12
JournalMolecular Therapy
Issue number12
StatePublished - Dec 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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