학술논문
Efficacy of dual intracerebroventricular and intravitreal CLN5 gene therapy in sheep prompts the first clinical trial to treat CLN5 Batten disease.
Document Type
Academic Journal
Author
Murray SJ; Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln, New Zealand.; Wellby MP; Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln, New Zealand.; Barrell GK; Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln, New Zealand.; Russell KN; Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln, New Zealand.; Deane AR; Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln, New Zealand.; Wynyard JR; Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln, New Zealand.; Gray SJ; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United States.; Palmer DN; Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln, New Zealand.; Department of Radiology, University of Otago, Christchurch, New Zealand.; Mitchell NL; Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln, New Zealand.; Department of Radiology, University of Otago, Christchurch, New Zealand.
Source
Publisher: Frontiers Media] Country of Publication: Switzerland NLM ID: 101548923 Publication Model: eCollection Cited Medium: Print ISSN: 1663-9812 (Print) Linking ISSN: 16639812 NLM ISO Abbreviation: Front Pharmacol Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
1663-9812
Abstract
Mutations in the CLN5 gene cause the fatal, pediatric, neurodegenerative disease CLN5 neuronal ceroid lipofuscinosis. Affected children suffer progressive neuronal loss, visual failure and premature death. Presently there is no treatment. This study evaluated dual intracerebroventricular (ICV) and intravitreal (IVT) administration of a self-complementary adeno-associated viral vector encoding ovine CLN5 (scAAV9/oCLN5) into CLN5 affected sheep (CLN5 -/- ) at various disease stages. CLN5 disease progression was slowed in pre-symptomatic sheep who received a moderate dose of scAAV9/oCLN5, whilst a higher ICV dose treatment in early and advanced symptomatic animals delayed or halted disease progression. Intracranial (brain) volume loss was attenuated in all treatment cohorts, and visual function was also sustained in both the early and advanced symptomatic treated sheep over the 24-month duration of the study. Robust CLN5 protein expression was detected throughout the brain and spinal cord, and improvements in central nervous system and retinal disease correlates were observed. These findings hold translational promise for extending and improving the quality of life in both pre-symptomatic and symptomatic CLN5 patients, and prompted the initiation of the first in-human Phase I/II clinical trial testing ICV/IVT administration of scAAV9 encoding human CLN5 (https://clinicaltrials.gov/; NCT05228145).
Competing Interests: NM and DP received research funding from Neurogene Inc. for this study. SG has received royalty income from Asklepios Biopharmaceutical Inc. for intellectual property (I.P.) that was not used in this study, and he received royalty income from Neurogene Inc. for I.P. that was used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Murray, Wellby, Barrell, Russell, Deane, Wynyard, Gray, Palmer and Mitchell.)
Competing Interests: NM and DP received research funding from Neurogene Inc. for this study. SG has received royalty income from Asklepios Biopharmaceutical Inc. for intellectual property (I.P.) that was not used in this study, and he received royalty income from Neurogene Inc. for I.P. that was used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Murray, Wellby, Barrell, Russell, Deane, Wynyard, Gray, Palmer and Mitchell.)