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

TitleDelayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke.
Publication TypeJournal Article
Year of Publication2016
AuthorsDuricki DA, Hutson TH, Kathe C, Soleman S, Gonzalez-Carter D, Petruska JC, H Shine D, Chen Q, Wood TC, Bernanos M, Cash D, Williams SCR, Gage FH, Moon LDF
IssuePt 1
Date Published2016 Jan
KeywordsAdenoviridae, Age Factors, Animals, Endothelin-1, Female, Genetic Vectors, Humans, Injections, Intramuscular, Locomotion, Magnetic Resonance Imaging, Microinjections, Muscle, Skeletal, Neuroimaging, Neurotrophin 3, Pyramidal Tracts, Rats, Recovery of Function, Spinal Cord, Stroke, Time Factors

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.

Alternate JournalBrain
PubMed ID26614754
PubMed Central IDPMC4785394
Grant List309731 / / European Research Council / International
/ / Arthritis Research UK / United Kingdom
/ / Chief Scientist Office / United Kingdom
/ / Medical Research Council / United Kingdom
Gage Laboratory