title: Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke.
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.
authors.affiliation: 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.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Duricki
authors.affiliation: 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.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hutson
authors.affiliation: 1 Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, 16-18 Newcomen Street, London SE1 1UL, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kathe
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Soleman
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez-Carter
authors.affiliation: 5 Department of Anatomical Sciences and Neurobiology, University of Louisville; Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, Louisville, Kentucky, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Petruska
authors.affiliation: 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.
authors.forename: H David
authors.initials: HD
authors.lastname: Shine
authors.affiliation: 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.
authors.forename: Qin
authors.initials: Q
authors.lastname: Chen
authors.affiliation: 7 Neuroimaging Research Group, King's College London, PO42 De Crespigny Park, London, SE5 8AF, UK.
authors.forename: Tobias C
authors.initials: TC
authors.lastname: Wood
authors.affiliation: 7 Neuroimaging Research Group, King's College London, PO42 De Crespigny Park, London, SE5 8AF, UK.
authors.forename: Michel
authors.initials: M
authors.lastname: Bernanos
authors.affiliation: 7 Neuroimaging Research Group, King's College London, PO42 De Crespigny Park, London, SE5 8AF, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Cash
authors.affiliation: 7 Neuroimaging Research Group, King's College London, PO42 De Crespigny Park, London, SE5 8AF, UK.
authors.forename: Steven C R
authors.initials: SC
authors.lastname: Williams
authors.affiliation: 8 The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.affiliation: 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.
authors.forename: Lawrence D F
authors.initials: LD
authors.lastname: Moon
mesh_terms: D000256:Adenoviridae; D000367:Age Factors; D000818:Animals; D019332:Endothelin-1 / Q000008:administration & dosage; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007273:Injections, Intramuscular; D008124:Locomotion / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008845:Microinjections; D018482:Muscle, Skeletal / Q000378:metabolism; D059906:Neuroimaging; D020933:Neurotrophin 3 / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D011712:Pyramidal Tracts / Q000187:drug effects; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects*; D013116:Spinal Cord / Q000378:metabolism; D020521:Stroke / Q000139:chemically induced / Q000188:drug therapy*; D013997:Time Factors
chemical_list: D019332:Endothelin-1; D020933:Neurotrophin 3
keywords: corticospinal; neurotrophin-3; plasticity; sprouting; stroke