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Human Molecular Genetics Advance Access published online on September 19, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl251
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received June 9, 2006
Revised September 7, 2006
Accepted September 7, 2006

Article

Lentiviral vector expressing retinoic acid receptor {beta}2 promotes recovery of function after corticospinal tract injury in the adult rat spinal cord

Ping K. Yip 1, Liang-Fong Wong 2 *, Damian Pattinson 1, Anna Battaglia 1, John Grist 1, Elizabeth J. Bradbury 1, Malcolm Maden 3, Stephen B. McMahon 1, and Nicholas D. Mazarakis 4

1 Neurorestoration Group, Wolfson CARD, King's College London, Guy's Campus, London Bridge, London SE1 1UL
2 Oxford BioMedica (UK) Ltd, Medawar Centre, Robert Robinson Avenue, The Oxford Science Park, Oxford OX4 4GA; Henry Wellcome LINE, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY
3 MRC Centre for Developmental Biology, King's College London, Guy's Campus, London Bridge, London SE1 1UL
4 Oxford BioMedica (UK) Ltd, Medawar Centre, Robert Robinson Avenue, The Oxford Science Park, Oxford OX4 4GA

* To whom correspondence should be addressed.
Liang-Fong Wong, E-mail: L.Wong{at}bristol.ac.uk


  Abstract

Spinal cord injury often results in permanent and devastating neurological deficits and disability. This is due to the limited regenerative capacity of neurones in the central nervous system (CNS). We recently demonstrated that a transcription factor retinoic receptor {beta}2 (RAR{beta}2) promoted axonal regeneration in adult sensory neurones located peripherally. However, it is not known if RAR{beta}2 can promote axonal regeneration in cortical neurones of the CNS. Here we demonstrate that delivery of RAR{beta}2 via a lentiviral vector to adult dissociated cortical neurones significantly enhances neurite outgrowth on adult cortical cryosections, which normally provide an unfavourable substrate for growth. We also show that lentiviral mediated transduction of corticospinal neurones resulted in robust transgene expression in layer V corticospinal neurones and their axonal projections in the corticospinal tract (CST) of the spinal cord. Expression of RAR{beta}2 in these neurones enhanced regeneration of the descending CST fibres after injury to these axons in the mid cervical spinal cord. Furthermore, we observed functional recovery in sensory and locomotor behavioural tests in RAR{beta}2 treated animals. These results suggest that a direct and selective delivery of RAR{beta}2 to the corticospinal neurones promotes long-distance functional regeneration of axons in the spinal cord and may thus offer new therapeutic gene strategy for the treatment of human spinal cord injuries.


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