AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease.

Autor:	Johnson TB; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA; Amicus Therapeutics, Philadelphia, PA, USA., White KA; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA., Brudvig JJ; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA., Cain JT; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA; Amicus Therapeutics, Philadelphia, PA, USA., Langin L; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA., Pratt MA; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA., Booth CD; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA., Timm DJ; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA., Davis SS; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA., Meyerink B; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA., Likhite S; The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Meyer K; The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Weimer JM; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA; Amicus Therapeutics, Philadelphia, PA, USA. Electronic address: jill.weimer@sanfordhealth.org.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2021 Jan 06; Vol. 29 (1), pp. 162-175. Date of Electronic Publication: 2020 Sep 24.
DOI:	10.1016/j.ymthe.2020.09.033
Abstrakt:	CLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with many cases resulting in premature death early in life. There are currently no treatments that can cure the disease or substantially slow disease progression. Using a mouse model of CLN8 disease, we tested the safety and efficacy of an intracerebroventricularly (i.c.v.) delivered self-complementary adeno-associated virus serotype 9 (scAAV9) gene therapy vector driving expression of human CLN8. A single neonatal injection was safe and well tolerated, resulting in robust transgene expression throughout the CNS from 4 to 24 months, reducing histopathological and behavioral hallmarks of the disease and restoring lifespan from 10 months in untreated animals to beyond 24 months of age in treated animals. While it is unclear whether some of these behavioral improvements relate to preserved visual function, improvements in learning/memory, or other central or peripheral benefits, these results demonstrate, by far, the most successful degree of rescue reported in an animal model of CLN8 disease, and they support further development of gene therapy for this disorder. (Copyright © 2020. Published by Elsevier Inc.)
Databáze:	MEDLINE
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