Journal
BRAIN
Volume 145, Issue 10, Pages 3405-3414Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awac182
Keywords
mitochondrial disease; Ndufs4; gene therapy; Complex I; Leigh disease
Categories
Funding
- Telethon Foundation [GGP19007, GGP20013]
- Fondation NRJ pour les Neurosciences - Institute de France Grant
- Associazione Luigi Comini Onlus
- Association Francaise contre les Myopathies [23706]
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Corra et al. have shown that double administration of a self-complementary adeno-associated viral 9 vector expressing human NDUFS4 can prevent the onset of Leigh-like disease in Ndufs4(-/-) mice and extend their healthy lifespan. This intervention has potential for further investigation in the prodromal phase of the disease in mice and eventually humans.
Corra et al. show that double administration of a self-complementary-adeno-associated viral 9 vector expressing human NDUFS4, via intra-vascular and intra-cerebroventricular injections on P1, prevents the onset of Leigh-like disease in Ndufs4(-/-) mice. The intervention extends healthy lifespan by several months compared to untreated mice. 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 approximate 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.
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