Enhanced Survival of the LINCL Mouse Following CLN2 Gene Transfer Using the rh.10 Rhesus Macaque-derived Adeno-associated Virus Vector
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Late infantile neuronal ceroid lipofuscinosis (LINCL) is a lysosomal storage disorder caused by mutations in the CLN2 gene and a deficiency of tripeptidyl peptidase I (TPP-I). Prior studies with adeno-associated virus (AAV) serotype 2 or 5 mediated transfer of the CLN2 complementary DNA to the central nervous system (CNS) of CLN2(-/-) mice cleared CNS storage granules, but provided no improvement in the phenotype or survival of this model of LINCL. In this study, AAV serotypes (AAV2, AAV5, AAV8, and AAVrh.10) were compared for the delivery of the same CLN2 expression cassette. AAVrh.10, derived from rhesus macaque, provided the highest TPP-I level and maximum spread beyond the site of injection. The AAVrh.10-based vector functioned equally well in naive rats and in rats previously immunized against human serotypes of AAV. When administered to the CNS of CLN2(-/-) mice, the AAVrh.10CLN2 vector provided widespread TPP-I activity comparable to that in the wild-type mice. Importantly, the AAVrh.10CLN2-treated CLN2(-/-) mice had significant reduction in CNS storage granules and demonstrated improvement in gait, nest-making abilities, seizures, balance beam function, and grip strength, as well as having a survival advantage.
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AAV8 and AAV9 exhibit a dominant neuronal tropism after direct injection into the rodent striatum as well as in other brain structures.
“AAV8 and AAV9 exhibit a dominant neuronal tropism after direct injection into the rodent striatum9,13,16,27 as well as in other brain structures.12,28,29”
From Characterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism (2016) · cites this paper as [27]
In prior studies, AAVrh.10 was found to be superior for widespread CNS expression compared with several serotypes, including AAV5.
“In prior studies, AAVrh.10 was found to be superior for widespread CNS expression than several serotypes, including AAV5.”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [32]
AAV9 and AAV.rh10 provided widespread expression patterns beyond the injection site with glia- and neuron-tropism respectively.
“On the contrary, AAV9 and AAV.rh10 provided widespread expression patterns beyond the injection site with glia- and neuron-tropism respectively [78, 79].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [79]
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References 44 · Cited by 170
- Authors
- Sondhi, D., Hackett, N. R., Peterson, D. A., Stratton, J., Baad, M., Travis, K. M., Wilson, J. M., & Crystal, R. G.
- Affiliations
- Cornell University (US)
- Rosalind Franklin University of Medicine and Science (US)
- University of Pennsylvania (US)
- Corresponding author
- Crystal, Ronald G
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 15
- Issue
- 3
- Pages
- 481-491
- ISSN
- 1525-0016 (ISSN-L)
- OpenAlex
- W2081200794
- Cited by
- 170
- References
- 44
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 5 · 2023: 5 · 2022: 8 · 2021: 5 · 2020: 8 · 2019: 8 · 2018: 9 · 2017: 8 · 2016: 11 · 2015: 12 · 2014: 19 · 2013: 14 · 2012: 12
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (U01NS047458)
- 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
- late infantile neuronal ceroid lipofuscinosis, tripeptidyl peptidase I, adeno-associated virus serotypes, gene therapy, lysosomal storage disease, survival, storage granules
- MeSH terms
- Tripeptidyl-Peptidase 1, Dependovirus, Aminopeptidases, Animals, Behavior, Animal, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Genetic Vectors, Macaca mulatta, Mice, Inbred C57BL, Neuronal Ceroid-Lipofuscinoses, Endopeptidases, Phenotype, Gene Expression, Survival Rate, Mice, Knockout, Transgenes, Mice, Serine Proteases
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