Intrathecal delivery of a bicistronic AAV9 vector expressing β-hexosaminidase A corrects Sandhoff disease in a murine model: A dosage study.

Autor:	Ryckman AE; Centre for Neuroscience Studies, Queen's University, Kingston, ON K7L 3N6, Canada., Deschenes NM; Centre for Neuroscience Studies, Queen's University, Kingston, ON K7L 3N6, Canada., Quinville BM; Centre for Neuroscience Studies, Queen's University, Kingston, ON K7L 3N6, Canada., Osmon KJL; Centre for Neuroscience Studies, Queen's University, Kingston, ON K7L 3N6, Canada., Mitchell M; Medical Genetics/Departments of Pediatrics, Queen's University, Kingston, ON K7L 2V7, Canada., Chen Z; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada., Gray SJ; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Walia JS; Centre for Neuroscience Studies, Queen's University, Kingston, ON K7L 3N6, Canada.; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.; Medical Genetics/Departments of Pediatrics, Queen's University, Kingston, ON K7L 2V7, Canada.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2023 Dec 05; Vol. 32 (1), pp. 101168. Date of Electronic Publication: 2023 Dec 05 (Print Publication: 2024).
DOI:	10.1016/j.omtm.2023.101168
Abstrakt:	The pathological accumulation of GM2 ganglioside associated with Tay-Sachs disease (TSD) and Sandhoff disease (SD) occurs in individuals who possess mutant forms of the heterodimer β-hexosaminidase A (Hex A) because of mutation of the HEXA and HEXB genes, respectively. With a lack of approved therapies, patients experience rapid neurological decline resulting in early death. A novel bicistronic vector carrying both HEXA and HEXB previously demonstrated promising results in mouse models of SD following neonatal intravenous administration, including significant reduction in GM2 accumulation, increased levels of Hex A, and a 2-fold extension of survival. The aim of the present study was to identify an optimal dose of the bicistronic vector in 6-week-old SD mice by an intrathecal route of administration along with transient immunosuppression, to inform possible clinical translation. Three doses of the bicistronic vector were tested: 2.5e11, 1.25e11, and 0.625e11 vector genomes per mouse. The highest dose provided the greatest increase in biochemical and behavioral parameters, such that treated mice lived to a median age of 56 weeks (>3 times the lifespan of the SD controls). These results have direct implications in deciding a human equivalent dose for TSD/SD and have informed the approval of a clinical trial application (NCT04798235). Competing Interests: The authors declare no competing interests. (© 2023 The Authors.)
Databáze:	MEDLINE
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