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Brain. 2016 Jan;139(Pt 1):259-75. doi: 10.1093/brain/awv341. Epub 2015 Nov 27.

Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke.

Author information

1
1 Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, 16-18 Newcomen Street, London SE1 1UL, UK 2 Centre for Integrative Biology, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
2
1 Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, 16-18 Newcomen Street, London SE1 1UL, UK 3 Division of Brain Sciences, Department of Medicine, Hammersmith Campus, Imperial College London, London, UK.
3
1 Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, 16-18 Newcomen Street, London SE1 1UL, UK.
4
1 Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, 16-18 Newcomen Street, London SE1 1UL, UK 4 John Van Geest Centre for Brain Repair University of Cambridge, The E.D. Adrian Building, Forvie Site, Robinson Way Cambridge, CB2 0PY, UK.
5
5 Department of Anatomical Sciences and Neurobiology, University of Louisville; Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, Louisville, Kentucky, USA.
6
6 Center for Cell and Gene Therapy, Department of Neuroscience, Alkek Bldg N1130.01, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
7
7 Neuroimaging Research Group, King's College London, PO42 De Crespigny Park, London, SE5 8AF, UK.
8
8 The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
9
1 Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, 16-18 Newcomen Street, London SE1 1UL, UK 2 Centre for Integrative Biology, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK lawrence.moon@kcl.ac.uk.

Abstract

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.

KEYWORDS:

corticospinal; neurotrophin-3; plasticity; sprouting; stroke

PMID:
26614754
PMCID:
PMC4785394
DOI:
10.1093/brain/awv341
[Indexed for MEDLINE]
Free PMC Article

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