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

Research output: Contribution to journalArticlepeer-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 languageEnglish
Pages (from-to)259-275
JournalBrain : a journal of neurology
Volume139
Issue number1
Early online date27 Nov 2015
DOIs
Accepted/In press29 Sep 2015
E-pub ahead of print27 Nov 2015
Published1 Jan 2016

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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.

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