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 journalArticle

42 Citations (Scopus)

Abstract

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
Volume21
Issue number12
DOIs
StatePublished - 2013

Fingerprint

Dependovirus
Canavan Disease
Genetic Therapy
Central Nervous System
Injections
Therapeutics
Myelin Sheath
MicroRNAs
Transgenes
Intravenous Injections
Neurodegenerative Diseases
Primates
Genes
Animal Models
Pediatrics
Lipids
Mutation
aspartoacylase

ASJC Scopus subject areas

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

Cite this

Ahmed, S. S., Li, H., Cao, C., Sikoglu, E. M., Denninger, A. R., Su, Q., ... Gao, G. (2013). A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS gene therapy in Canavan mice. Molecular Therapy, 21(12), 2136-2147. https://doi.org/10.1038/mt.2013.138

A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS gene therapy in Canavan mice. / 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; Kirschner, Daniel A.; Seyfried, Thomas N.; Flotte, Terence R.; Matalon, Reuben; Gao, Guangping.

In: Molecular Therapy, Vol. 21, No. 12, 2013, p. 2136-2147.

Research output: Contribution to journalArticle

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 2013, 'A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS gene therapy in Canavan mice', Molecular Therapy, vol. 21, no. 12, pp. 2136-2147. https://doi.org/10.1038/mt.2013.138
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 ; Kirschner, Daniel A. ; Seyfried, Thomas N. ; Flotte, Terence R. ; Matalon, Reuben ; Gao, Guangping. / A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS gene therapy in Canavan mice. In: Molecular Therapy. 2013 ; Vol. 21, No. 12. pp. 2136-2147.
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abstract = "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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