365. Long-Term Toxicology Evaluation of AAVrh. 10hARSA Administration to the CNS of Nonhuman Primates to Treat Metachromatic Leukodystrophy
Open accessAbstract
Metachromatic leukodystrophy (MLD), a lysosomal storage disorder caused by the deficiency of the enzyme arylsulfatase A (ARSA), is a recessive, fatal neurodegenerative lysosomal storage disease associated with intracellular accumulation of sulfatides in the CNS. The disease is fatal, with no approved therapy. The focus of this study is to test the hypothesis that direct CNS administration of AAVrh.10hARSA (AAVrh.10 serotype vector coding for the human ARSA cDNA) to the CNS of nonhuman primates at doses scalable to humans has an acceptable long term safety profile.
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The values from the control animal in this study and controls in previous studies with African Green monkeys were used to calculate normal ranges and establish upper and lower limits of normal African Green monkey values for comparisons of pre- and post-surgery blood/serum parameters.
“The values from the control animal in this study and controls in previous studies with African Green monkeys were used to calculate normal ranges (total 65 blood samples from 29 individual male NHPs) and establish the upper and lower limits of normal African Green monkey values for comparisons of pre- and post-surgery blood/serum parameters.31,35”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [35]
The vector-administered groups (all routes) did not differ from the sham controls in any parameter of general assessment or comprehensive blood profile, remaining within the historic ranges.
“The vector-administered groups (all routes) did not differ from the sham controls (n = 2) in any parameter of general assessment or comprehensive blood profile (complete blood count and chemistry panel), remaining within the historic ranges obtained from previous studies (Supplementary Figs. S10 and S11).31,35”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [35]
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AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease
Rosenberg, J. B., Kaplitt, M. G., De, B. P., Chen, A., Flagiello, T., Salami, C., Pey, E., Zhao, L., Ricart Arbona, R. J., Monette, S., et al. (2018) · Human Gene Therapy Clinical Development · doi:10.1089/humc.2017.231 · Cited by 169 · see citing works
“The values from the control animal in this study and controls in previous studies with African Green monkeys were used to calculate normal ranges (total 65 blood samples from 29 individual male NHPs) and establish the upper and lower limits of normal African Green monkey values for comparisons of preand post-surgery b…”
MethodResultInfluentialSelf-citationBallon, D., Rosenberg, J. B., Fung, E. K., Nikolopoulou, A., Kothari, P. J., De, B. P., He, B., Chen, A., Heier, L., Sondhi, D., et al. (2020) · Human Gene Therapy · doi:10.1089/hum.2020.116 · Cited by 37 · see citing works
Self-citationCrystal, R. G. (2020) · Human Gene Therapy · doi:10.1089/hum.2020.29112.rgc · Cited by 1 · see citing works
Self-citation
- Authors
- Sondhi, D., Rosenberg, J. B., De, B. P., Monette, S., Chen, A., Flagiello, T., Caffrey, E., Kaminsky, S. M., Aubourg, P., & Crystal, R. G.
- Affiliations
- Weill Cornell Medicine (US)
- Inserm (FR)
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 24
- Pages
- S146
- ISSN
- 1525-0016 (ISSN-L)
- OpenAlex
- W2561345008
- Cited by
- 3
- References
- 0
- Citations by year
- 2020: 2 · 2018: 1
- FWCI
- 0.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- 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
- metachromatic leukodystrophy, arylsulfatase A, recombinant adeno-associated virus vectors, CNS gene therapy, chronic toxicity, non-human primates, lysosomal storage disease, sulfatide accumulation, neurodegeneration, vector safety
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