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Delayed viral vector mediated delivery of neurotrophin-3 improves skilled hindlimb function and stability after thoracic contusion

Research output: Contribution to journalArticlepeer-review

Jared Sydney-Smith, Alice Koltchev, Lawrence D F Moon, Philippa Warren

Original languageEnglish
Article number114278
JournalExperimental Neurology
Accepted/In press19 Nov 2022
PublishedFeb 2023

Bibliographical note

Funding Information: MRC project grant (MR/S011110/1) and King’s College London Prize Fellowship to P.M.W; and a Nathalie Rose Barr PhD studentship from the Spinal Research Trust (NRB117 to LDFM for JS-S). Funding Information: The authors wish to thank Dr. Aline Spejo for her assistance with the ELISA experiments. We are grateful to the veterinary and technical staff at King's College London for their proficiency and care of the animals. We acknowledge the Penn Vector Core in the Gene Therapy Program of the University of Pennsylvania for production of the AAVs for this project. We thank Dr Diana Cash and Dr Eugene Kim (King's College London preclinical imaging core) for their help with acquisition of magnetic resonance images. Publisher Copyright: © 2022


  • Sydney-Smith et al. 2022

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    Uploaded date:14 Dec 2022

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King's Authors


Intramuscular injection of an Adeno-associated viral vector serotype 1 (AAV1) encoding Neurotrophin-3 (NT3) into hindlimb muscles 24 h after a severe T9 spinal level contusion in rats has been shown to induce lumbar spinal neuroplasticity, partially restore locomotive function and reduce spasms during swimming. Here we investigate whether a targeted delivery of NT3 to lumbar and thoracic motor neurons 48 h following a severe contusive injury aids locomotive recovery in rats. AAV1-NT3 was injected bilaterally into the tibialis anterior, gastrocnemius and rectus abdominus muscles 48-h following trauma, persistently elevating serum levels of the neurotrophin. NT3 modestly improved trunk stability, accuracy of stepping during skilled locomotion, and alternation of the hindlimbs during swimming, but it had no effect on gross locomotor function in the open field. The number of vGlut1 + boutons, likely arising from proprioceptive afferents, on gastrocnemius α-motor neurons was increased after injury but normalised following NT3 treatment, suggestive of a mechanism in which functional benefits may be mediated through proprioceptive feedback. Ex vivo MRI revealed substantial loss of grey and white matter at the lesion epicentre but no effect of delayed NT3 treatment to induce neuroprotection. Lower body spasms and hyperreflexia of an intrinsic paw muscle were not reliably induced in this severe injury model suggesting a more complex anatomical or physiological cause to their induction. We have shown that delayed intramuscular AAV-NT3 treatment can promote recovery in skilled stepping and coordinated swimming, supporting a role for NT3 as a therapeutic strategy for spinal injuries potentially through modulation of somatosensory feedback.

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