In vivo base editing of a pathogenic Eif2b5 variant improves vanishing white matter phenotypes in mice.

Autor:	Böck D; Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland., Revers IM; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, 1105AZ Amsterdam, the Netherlands., Bomhof ASJ; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, 1105AZ Amsterdam, the Netherlands., Hillen AEJ; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, 1105AZ Amsterdam, the Netherlands., Boeijink C; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, 1105AZ Amsterdam, the Netherlands., Kissling L; Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland., Egli S; Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland., Moreno-Mateos MA; Andalusian Center for Developmental Biology (CABD), Pablo de Olavide University/CSIC/Junta de Andalucía, 41013 Seville, Spain; Department of Molecular Biology and Biochemical Engineering, Pablo de Olavide University, 41013 Seville, Spain., van der Knaap MS; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, 1105AZ Amsterdam, the Netherlands; Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081HV Amsterdam, the Netherlands., van Til NP; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, 1105AZ Amsterdam, the Netherlands; Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081HV Amsterdam, the Netherlands. Electronic address: n.p.vantil@amsterdamumc.nl., Schwank G; Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland. Electronic address: schwank@pharma.uzh.ch.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 May 01; Vol. 32 (5), pp. 1328-1343. Date of Electronic Publication: 2024 Mar 07.
DOI:	10.1016/j.ymthe.2024.03.009
Abstrakt:	Vanishing white matter (VWM) is a fatal leukodystrophy caused by recessive mutations in subunits of the eukaryotic translation initiation factor 2B. Currently, there are no effective therapies for VWM. Here, we assessed the potential of adenine base editing to correct human pathogenic VWM variants in mouse models. Using adeno-associated viral vectors, we delivered intein-split adenine base editors into the cerebral ventricles of newborn VWM mice, resulting in 45.9% ± 5.9% correction of the Eif2b5 R191H variant in the cortex. Treatment slightly increased mature astrocyte populations and partially recovered the integrated stress response (ISR) in female VWM animals. This led to notable improvements in bodyweight and grip strength in females; however, locomotor disabilities were not rescued. Further molecular analyses suggest that more precise editing (i.e., lower rates of bystander editing) as well as more efficient delivery of the base editors to deep brain regions and oligodendrocytes would have been required for a broader phenotypic rescue. Our study emphasizes the potential, but also identifies limitations, of current in vivo base-editing approaches for the treatment of VWM or other leukodystrophies. Competing Interests: Declaration of interests G.S. is a scientific advisor to Prime Medicine. (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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