Gene Therapy Corrects Brain and Behavioral Pathologies in CLN6-Batten Disease.

Autor:	Cain JT; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA., Likhite S; The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA., White KA; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA., Timm DJ; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA., Davis SS; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA., Johnson TB; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA., Dennys-Rivers CN; The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA., Rinaldi F; The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA., Motti D; The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA., Corcoran S; The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA., Morales P; The Mannheimer Foundation, Inc., Homestead, FL 33034, USA., Pierson C; The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA., Hughes SM; Department of Biochemistry, School of Biomedical Sciences, Brain Health Research Centre, University of Otago, Dunedin 9016, New Zealand., Lee SY; Division of Biology, Kansas State University, Manhattan, KS 66506, USA., Kaspar BK; AveXis Inc., Bannockburn, IL 60015, USA., Meyer K; The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA., Weimer JM; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA; Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57069, USA. Electronic address: jill.weimer@sanfordhealth.org.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2019 Oct 02; Vol. 27 (10), pp. 1836-1847. Date of Electronic Publication: 2019 Jul 10.
DOI:	10.1016/j.ymthe.2019.06.015
Abstrakt:	CLN6-Batten disease, a form of neuronal ceroid lipofuscinosis is a rare lysosomal storage disorder presenting with gradual declines in motor, visual, and cognitive abilities and early death by 12-15 years of age. We developed a self-complementary adeno-associated virus serotype 9 (scAAV9) vector expressing the human CLN6 gene under the control of a chicken β-actin (CB) hybrid promoter. Intrathecal delivery of scAAV9.CB.hCLN6 into the cerebrospinal fluid (CSF) of the lumbar spinal cord of 4-year-old non-human primates was safe, well tolerated, and led to efficient targeting throughout the brain and spinal cord. A single intracerebroventricular (i.c.v.) injection at post-natal day 1 in Cln6 mutant mice delivered scAAV9.CB.CLN6 directly into the CSF, and it prevented or drastically reduced all of the pathological hallmarks of Batten disease. Moreover, there were significant improvements in motor performance, learning and memory deficits, and survival in treated Cln6 mutant mice, extending survival from 15 months of age (untreated) to beyond 21 months of age (treated). Additionally, many parameters were similar to wild-type counterparts throughout the lifespan of the treated mice. (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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