Double administration of self-complementary AAV9NDUFS4 prevents Leigh disease in Ndufs4-/- mice.

Autor:	Corrà S; Venetian Institute of Molecular Medicine, 35128 Padova, Italy., Cerutti R; Venetian Institute of Molecular Medicine, 35128 Padova, Italy.; Department of Neurosciences, University of Padova, 35128 Padova, Italy., Balmaceda V; Venetian Institute of Molecular Medicine, 35128 Padova, Italy., Viscomi C; Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.; Study Centre for Neurodegeneration, Univcersity of Padova (CESNE), 35131, Padova, Italy., Zeviani M; Venetian Institute of Molecular Medicine, 35128 Padova, Italy.; Department of Neurosciences, University of Padova, 35128 Padova, Italy.; Study Centre for Neurodegeneration, Univcersity of Padova (CESNE), 35131, Padova, Italy.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2022 Oct 21; Vol. 145 (10), pp. 3405-3414.
DOI:	10.1093/brain/awac182
Abstrakt:	Leigh disease, or subacute necrotizing encephalomyelopathy, a genetically heterogeneous condition consistently characterized by defective mitochondrial bioenergetics, is the most common oxidative-phosphorylation related disease in infancy. Both neurological signs and pathological lesions of Leigh disease are mimicked by the ablation of the mouse mitochondrial respiratory chain subunit Ndufs4-/-, which is part of, and crucial for, normal Complex I activity and assembly, particularly in the brains of both children and mice. We previously conveyed the human NDUFS4 gene to the mouse brain using either single-stranded adeno-associated viral 9 recombinant vectors or the PHP.B adeno-associated viral vector. Both these approaches significantly prolonged the lifespan of the Ndufs4-/- mouse model but the extension of the survival was limited to a few weeks by the former approach, whereas the latter was applicable to a limited number of mouse strains, but not to primates. Here, we exploited the recent development of new, self-complementary adeno-associated viral 9 vectors, in which the transcription rate of the recombinant gene is markedly increased compared with the single-stranded adeno-associated viral 9 and can be applied to all mammals, including humans. Either single intra-vascular or double intra-vascular and intra-cerebro-ventricular injections were performed at post-natal Day 1. The first strategy ubiquitously conveyed the human NDUFS4 gene product in Ndufs4-/- mice, doubling the lifespan from 45 to ≈100 days after birth, when the mice developed rapidly progressive neurological failure. However, the double, contemporary intra-vascular and intra-cerebroventricular administration of self-complementary-adeno-associated viral NDUFS4 prolonged healthy lifespan up to 9 months of age. These mice were well and active at euthanization, at 6, 7, 8 and 9 months of age, to investigate the brain and other organs post-mortem. Robust expression of hNDUFS4 was detected in different cerebral areas preserving normal morphology and restoring Complex I activity and assembly. Our results warrant further investigation on the translatability of self-complementary-adeno-associated viral 9 NDUFS4-based therapy in the prodromal phase of the disease in mice and eventually humans. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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