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 | |
| State | Published - 2013 |
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ASJC Scopus subject areas
- Molecular Biology
- Molecular Medicine
- Genetics
- Drug Discovery
- Pharmacology
Cite this
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 journal › Article
}
TY - JOUR
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
PY - 2013
Y1 - 2013
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.
UR - http://www.scopus.com/inward/record.url?scp=84890120669&partnerID=8YFLogxK
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U2 - 10.1038/mt.2013.138
DO - 10.1038/mt.2013.138
M3 - Article
VL - 21
SP - 2136
EP - 2147
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 12
ER -