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

doi:10.1038/mt.2013.138

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

Pediatrics

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

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 language	English (US)
Pages (from-to)	2136-2147
Number of pages	12
Journal	Molecular Therapy
Volume	21
Issue number	12
DOIs	https://doi.org/10.1038/mt.2013.138
State	Published - Dec 2013

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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Ahmed, S. S., Li, H., Cao, C., Sikoglu, E. M., Denninger, A. R., Su, Q., Eaton, S., Liso Navarro, A. A., Xie, J., Szucs, S., Zhang, H., Moore, C., Kirschner, D. A., Seyfried, T. N., Flotte, T. R., 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, 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, 12.2013, p. 2136-2147.

Research output: Contribution to journal › Article › peer-review

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

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.",

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

note = "Funding Information: We acknowledge Aryan Namboodiri and John Moffett for kindly supplying us with the aspartoacylase antibody. We also acknowledge Bryan Tan for his assistance with X-ray diffraction analysis. The study was funded by an internal grant from University of Massachusetts, grants from Jacob{\textquoteright}s Cure, NTSAD Foundation, and Canavan Foundation and National Institutes of Health R01 grant (1R01NS076991) to G.G., and partially supported by a grant from National High Technology Research and Development Program (“863” Program) of China (2012AA020810) to G.G. The electron microscopy was supported by Award Number S10RR027897 from the National Center for Research Resources. X-ray diffraction analysis was supported by a grant from the European Leukodystrophy Association (ELA), #ELA2010-042C5B (D.A.K.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The authors declared no conflict of interest.",

year = "2013",

month = dec,

doi = "10.1038/mt.2013.138",

language = "English (US)",

volume = "21",

pages = "2136--2147",

journal = "Molecular Therapy",

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T1 - A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS gene therapy in Canavan mice

AU - Ahmed, Seemin Seher

AU - Li, Huapeng

AU - Cao, Chunyan

AU - Sikoglu, Elif M.

AU - Denninger, Andrew R.

AU - Su, Qin

AU - Eaton, Samuel

AU - Liso Navarro, Ana A.

AU - Xie, Jun

AU - Szucs, Sylvia

AU - Zhang, Hongwei

AU - Moore, Constance

AU - Kirschner, Daniel A.

AU - Seyfried, Thomas N.

AU - Flotte, Terence R.

AU - Matalon, Reuben

AU - Gao, Guangping

N1 - Funding Information: We acknowledge Aryan Namboodiri and John Moffett for kindly supplying us with the aspartoacylase antibody. We also acknowledge Bryan Tan for his assistance with X-ray diffraction analysis. The study was funded by an internal grant from University of Massachusetts, grants from Jacob’s Cure, NTSAD Foundation, and Canavan Foundation and National Institutes of Health R01 grant (1R01NS076991) to G.G., and partially supported by a grant from National High Technology Research and Development Program (“863” Program) of China (2012AA020810) to G.G. The electron microscopy was supported by Award Number S10RR027897 from the National Center for Research Resources. X-ray diffraction analysis was supported by a grant from the European Leukodystrophy Association (ELA), #ELA2010-042C5B (D.A.K.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The authors declared no conflict of interest.

PY - 2013/12

Y1 - 2013/12

N2 - 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.

AB - 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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