Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke
Author(s)
Type
Journal Article
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.
Date Issued
2015-11-27
Date Acceptance
2015-09-29
Citation
Brain, 2015, 139, pp.259-275
ISSN
0006-8950
Publisher
Oxford University Press
Start Page
259
End Page
275
Journal / Book Title
Brain
Volume
139
Copyright Statement
© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000370205000033&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Neurosciences & Neurology
Neurotrophin-3
Stroke
Plasticity
Corticospinal
Sprouting
Spinal-cord-injury
Retrograde axonal-transport
Cerebral-artery occlusion
Central-nervous-system
Sensory neurons
Anterograde transport
Corticospinal tract
Blood-brain
Synaptic-transmission
Neurology & Neurosurgery
Medical And Health Sciences
Psychology And Cognitive Sciences
Publication Status
Published