Intrathecal administration of AAV/GALC vectors in 10-11-day-old twitcher mice improves survival and is enhanced by bone marrow transplant
Open accessAbstract
Globoid cell leukodystrophy (GLD), or Krabbe disease, is an autosomal recessive neurodegenerative disease caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). Hematopoietic stem cell transplantation (HSCT) provides modest benefit in presymptomatic patients but is well short of a cure. Gene transfer experiments using viral vectors have shown some success in extending the survival in the mouse model of GLD, twitcher mice. The present study compares three single-stranded (ss) AAV serotypes, two natural and one engineered (with oligodendrocyte tropism), and a self-complementary (sc) AAV vector, all packaged with a codon-optimized murine GALC gene. The vectors were delivered via a lumbar intrathecal route for global CNS distribution on PND10-11 at a dose of 2 × 10(11) vector genomes (vg) per mouse. The results showed a similar significant extension of life span of the twitcher mice for all three serotypes (AAV9, AAVrh10, and AAV-Olig001) as well as the scAAV9 vector, compared to control cohorts. The rAAV gene transfer facilitated GALC biodistribution and detectable enzymatic activity throughout the CNS as well as in sciatic nerve and liver. When combined with BMT from syngeneic wild-type mice, there was significant improvement in survival for ssAAV9. Histopathological analysis of brain, spinal cord, and sciatic nerve showed significant improvement in preservation of myelin, with ssAAV9 providing the greatest benefit. In summary, we demonstrate that lumbar intrathecal delivery of rAAV/mGALCopt can significantly enhance the life span of twitcher mice treated at PND10-11 and that BMT synergizes with this treatment to improve the survival further. © 2016 Wiley Periodicals, Inc.
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AAV/Olig001 has been shown to partially rescue the phenotype in a mouse model of lysosomal storage disease.
“AAV/Olig001 has been shown to partially rescue the phenotype in a mouse model of lysosomal storage disease”
From Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease (2021) · cites this paper as [9]
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- Authors
- Karumuthil‐Melethil, S., Marshall, M. S., Heindel, C., Jakubauskas, B., Bongarzone, E. R., & Gray, S. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Illinois Chicago (US)
- Corresponding author
- Gray, Steven J.
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2016-09-17
- Volume
- 94
- Issue
- 11
- Pages
- 1138-1151
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- PMC
- PMC5028109
- OpenAlex
- W2523437487
- Cited by
- 51
- References
- 45
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 2 · 2023: 6 · 2022: 4 · 2021: 14 · 2020: 9 · 2019: 4 · 2018: 2 · 2017: 1
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Hunter's Hope Foundation
- Legacy of Angels Foundation
- National Institutes of Health (F30NS090684, R01NS065808, R21NS087474)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Krabbe disease, galactocerebrosidase, adeno-associated virus vectors, intrathecal gene delivery, twitcher mouse, bone marrow transplantation, AAV9, AAVrh10, self-complementary AAV, codon optimization, myelin preservation, survival extension, lysosomal storage disease
- MeSH terms
- Dependovirus, Animals, Animals, Newborn, Disease Models, Animal, Galactosylceramidase, Genetic Vectors, Injections, Spinal, Leukodystrophy, Globoid Cell, Mice, Mutant Strains, RNA, Messenger, Genetic Therapy, Survival Analysis, Bone Marrow Transplantation, Treatment Outcome, Mice
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