期刊
BRAIN
卷 139, 期 -, 页码 259-275出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awv341
关键词
neurotrophin-3; stroke; plasticity; corticospinal; sprouting
资金
- European Research Council under the European Union's Seventh Framework Programme (FP) / ERC Grant [309731]
- Research Councils UK Academic Fellowship
- Medical Research Council (MRC)
- British Pharmacological Society (BPS)'s Integrative Pharmacology Fund
- Christopher and Dana Reeve Foundation
- International Spinal Research Trust
- Rosetrees Trust
- JPB Foundation
- Helmsely Charitable Trust
- Lookout Fund
- Capacity Building Award in Integrative Mammalian Biology - Biotechnology and Biological Sciences Research Council
- BPS
- Higher Education Funding Council for England
- Knowledge Transfer Partnerships
- MRC
- Scottish Funding Council
- MRC [G0600998] Funding Source: UKRI
- Medical Research Council [G0600998] Funding Source: researchfish
There is an urgent need for a therapy that reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. We show here that intramuscular delivery of neurotrophin-3 (NT3, encoded by NTF3) can induce sensorimotor recovery when treatment is initiated 24 h after stroke. Specifically, in two randomized, blinded preclinical trials, we show improved sensory and locomotor function in adult (6 months) and elderly (18 months) rats treated 24 h following cortical ischaemic stroke with human NT3 delivered using a clinically approved serotype of adeno-associated viral vector (AAV1). Importantly, AAV1-hNT3 was given in a clinically-feasible timeframe using a straightforward, targeted route (injections into disabled forelimb muscles). Magnetic resonance imaging and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, treatment caused corticospinal axons from the less affected hemisphere to sprout in the spinal cord. This treatment is the first gene therapy that reverses disability after stroke when administered intramuscularly in an elderly body. Importantly, phase I and II clinical trials by others show that repeated, peripherally administered high doses of recombinant NT3 are safe and well tolerated in humans with other conditions. This paves the way for NT3 as a therapy for stroke.
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