Research output: Contribution to journal › Article › peer-review
Denise A Duricki, Thomas H Hutson, Claudia Kathe, Sara Soleman, Daniel Gonzalez-Carter, Jeffrey C Petruska, H David Shine, Qin Chen, Tobias C Wood, Michel Bernanos, Diana Cash, Steven C R Williams, Fred H Gage, Lawrence D F Moon
Original language | English |
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Pages (from-to) | 259-275 |
Journal | Brain : a journal of neurology |
Volume | 139 |
Issue number | 1 |
Early online date | 27 Nov 2015 |
DOIs | |
Accepted/In press | 29 Sep 2015 |
E-pub ahead of print | 27 Nov 2015 |
Published | 1 Jan 2016 |
Delayed intramuscular human neurotrophin-3_DURICKI_Accepted29September2015_GOLD VoR
259.full.pdf, 2.19 MB, application/pdf
Uploaded date:20 Jul 2016
Version:Final published version
Licence:CC BY
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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