Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis
Abstract
:1. Introduction
2. Results
2.1. scAAV9.hGM2A Efficiently Distributes to the CNS of Gm2a−/− Mice Fourteen Weeks after Treatment and Remains Detectable for Their Lifespan
2.2. scAAV9.hGM2A Mediates Expression of Human GM2AP in Gm2a−/− Mice
2.3. scAAV9.hGM2A Dose-Dependently Diminishes GM2 Accumulation in Gm2a−/− Mice
2.4. scAAV9.hGM2A Is Tolerable over the Lifespan of Treated Animals
2.5. Similar Comorbidity Profiles of scAAV9.hGM2A-Treated and Untreated Cohorts Support Its Safety as a Gene Therapy
3. Discussion
4. Materials and Methods
4.1. Plasmid Construct
4.2. Mice
- Gm2a Mutation Forward 5′-CTTGGGTGGAGAGGCTATTC-3′
- Gm2a Mutation Reverse 5′-AGGTGAGATGACAGGAGATC-3′
- Gm2a WT Forward 5′-TACCTACTCACTACCCACGAGC-3′
- Gm2a WT Reverse 5′-ACACAGAAGAAGAGGCCTGC-3′
4.3. Drug Administration
4.4. Immunosuppressant Administration
4.5. Behavioural Testing
4.6. Euthanization
4.7. Vector Biodistribution
- GM2A WT forward 5′-TATGGGCTTCCTTGCCACTG-3′
- GM2A WT reverse 5′-CTCAGGACGCTCTCTATGCG-3′
- Mouse LaminB2 primers used for quantification of mouse genomic DNA are as follows:
- LaminB2 WT forward 5′-GGACCCAAGGACTACCTCAAGGG-3′
- LaminB2 WT reverse 5′-AGGGCACCTCCATCTCGGAAAC-3′.
- Data is shown as the number of viral genomes (vector DNA copies) per mouse genome (vg/mouse).
4.8. Western Blot
4.9. Ganglioside Quantification Assay
4.10. Histology
4.11. Statistics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Deschenes, N.M.; Cheng, C.; Ryckman, A.E.; Quinville, B.M.; Khanal, P.; Mitchell, M.; Chen, Z.; Sangrar, W.; Gray, S.J.; Walia, J.S. Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis. Int. J. Mol. Sci. 2023, 24, 9217. https://doi.org/10.3390/ijms24119217
Deschenes NM, Cheng C, Ryckman AE, Quinville BM, Khanal P, Mitchell M, Chen Z, Sangrar W, Gray SJ, Walia JS. Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis. International Journal of Molecular Sciences. 2023; 24(11):9217. https://doi.org/10.3390/ijms24119217
Chicago/Turabian StyleDeschenes, Natalie M., Camilyn Cheng, Alex E. Ryckman, Brianna M. Quinville, Prem Khanal, Melissa Mitchell, Zhilin Chen, Waheed Sangrar, Steven J. Gray, and Jagdeep S. Walia. 2023. "Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis" International Journal of Molecular Sciences 24, no. 11: 9217. https://doi.org/10.3390/ijms24119217
APA StyleDeschenes, N. M., Cheng, C., Ryckman, A. E., Quinville, B. M., Khanal, P., Mitchell, M., Chen, Z., Sangrar, W., Gray, S. J., & Walia, J. S. (2023). Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis. International Journal of Molecular Sciences, 24(11), 9217. https://doi.org/10.3390/ijms24119217