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Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease

CLN5 neuronal ceroid lipofuscinosis (NCL, Batten disease) is a rare, inherited fatal neurodegenerative disorder caused by mutations in the CLN5 gene. The disease is characterised by progressive neuronal loss, blindness, and premature death. There is no cure. This study evaluated the efficacy of intr...

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Autores principales: Mitchell, Nadia L., Murray, Samantha J., Wellby, Martin P., Barrell, Graham K., Russell, Katharina N., Deane, Ashley R., Wynyard, John R., Palmer, Madeleine J., Pulickan, Anila, Prendergast, Phillipa M., Casy, Widler, Gray, Steven J., Palmer, David N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10442658/
https://www.ncbi.nlm.nih.gov/pubmed/37614821
http://dx.doi.org/10.3389/fgene.2023.1212228
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author Mitchell, Nadia L.
Murray, Samantha J.
Wellby, Martin P.
Barrell, Graham K.
Russell, Katharina N.
Deane, Ashley R.
Wynyard, John R.
Palmer, Madeleine J.
Pulickan, Anila
Prendergast, Phillipa M.
Casy, Widler
Gray, Steven J.
Palmer, David N.
author_facet Mitchell, Nadia L.
Murray, Samantha J.
Wellby, Martin P.
Barrell, Graham K.
Russell, Katharina N.
Deane, Ashley R.
Wynyard, John R.
Palmer, Madeleine J.
Pulickan, Anila
Prendergast, Phillipa M.
Casy, Widler
Gray, Steven J.
Palmer, David N.
author_sort Mitchell, Nadia L.
collection PubMed
description CLN5 neuronal ceroid lipofuscinosis (NCL, Batten disease) is a rare, inherited fatal neurodegenerative disorder caused by mutations in the CLN5 gene. The disease is characterised by progressive neuronal loss, blindness, and premature death. There is no cure. This study evaluated the efficacy of intracerebroventricular (ICV) delivery of an adeno-associated viral vector encoding ovine CLN5 (scAAV9/oCLN5) in a naturally occurring sheep model of CLN5 disease. CLN5 affected (CLN5(−/−)) sheep received low, moderate, or high doses of scAAV9/oCLN5 at three disease stages. The treatment delayed disease progression, extended survival and slowed stereotypical brain atrophy in most animals. Of note, one high dose treated animal only developed mild disease symptomology and survived to 60.1 months of age, triple the natural life expectancy of an untreated CLN5(−/−) sheep. Eyesight was not preserved at any administration age or dosage. Histopathologic examination revealed that greater transduction efficiency was achieved through higher ICV doses, and this resulted in greater amelioration of disease pathology. Together with other pre-clinical data from CLN5(−/−) sheep, the safety and efficacy data from these investigational new drug (IND)-enabling studies supported the initiation of the first in-human CLN5 gene therapy clinical study using the ICV delivery route for the treatment of CLN5 NCL. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05228145
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spelling pubmed-104426582023-08-23 Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease Mitchell, Nadia L. Murray, Samantha J. Wellby, Martin P. Barrell, Graham K. Russell, Katharina N. Deane, Ashley R. Wynyard, John R. Palmer, Madeleine J. Pulickan, Anila Prendergast, Phillipa M. Casy, Widler Gray, Steven J. Palmer, David N. Front Genet Genetics CLN5 neuronal ceroid lipofuscinosis (NCL, Batten disease) is a rare, inherited fatal neurodegenerative disorder caused by mutations in the CLN5 gene. The disease is characterised by progressive neuronal loss, blindness, and premature death. There is no cure. This study evaluated the efficacy of intracerebroventricular (ICV) delivery of an adeno-associated viral vector encoding ovine CLN5 (scAAV9/oCLN5) in a naturally occurring sheep model of CLN5 disease. CLN5 affected (CLN5(−/−)) sheep received low, moderate, or high doses of scAAV9/oCLN5 at three disease stages. The treatment delayed disease progression, extended survival and slowed stereotypical brain atrophy in most animals. Of note, one high dose treated animal only developed mild disease symptomology and survived to 60.1 months of age, triple the natural life expectancy of an untreated CLN5(−/−) sheep. Eyesight was not preserved at any administration age or dosage. Histopathologic examination revealed that greater transduction efficiency was achieved through higher ICV doses, and this resulted in greater amelioration of disease pathology. Together with other pre-clinical data from CLN5(−/−) sheep, the safety and efficacy data from these investigational new drug (IND)-enabling studies supported the initiation of the first in-human CLN5 gene therapy clinical study using the ICV delivery route for the treatment of CLN5 NCL. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05228145 Frontiers Media S.A. 2023-08-08 /pmc/articles/PMC10442658/ /pubmed/37614821 http://dx.doi.org/10.3389/fgene.2023.1212228 Text en Copyright © 2023 Mitchell, Murray, Wellby, Barrell, Russell, Deane, Wynyard, Palmer, Pulickan, Prendergast, Casy, Gray and Palmer. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Mitchell, Nadia L.
Murray, Samantha J.
Wellby, Martin P.
Barrell, Graham K.
Russell, Katharina N.
Deane, Ashley R.
Wynyard, John R.
Palmer, Madeleine J.
Pulickan, Anila
Prendergast, Phillipa M.
Casy, Widler
Gray, Steven J.
Palmer, David N.
Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease
title Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease
title_full Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease
title_fullStr Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease
title_full_unstemmed Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease
title_short Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease
title_sort long-term safety and dose escalation of intracerebroventricular cln5 gene therapy in sheep supports clinical translation for cln5 batten disease
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10442658/
https://www.ncbi.nlm.nih.gov/pubmed/37614821
http://dx.doi.org/10.3389/fgene.2023.1212228
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