Human Molecular Genetics Advance Access originally published online on September 19, 2006
Human Molecular Genetics 2006 15(21):3107-3118; doi:10.1093/hmg/ddl251
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Lentiviral vector expressing retinoic acid receptor ß2 promotes recovery of function after corticospinal tract injury in the adult rat spinal cord
1 Neurorestoration Group, Wolfson CARD, 2 MRC Centre for Developmental Biology, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK, 3 Oxford BioMedica (UK) Ltd, Medawar Centre, Robert Robinson Avenue, The Oxford Science Park, Oxford OX4 4GA, UK and 4 Henry Wellcome LINE, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK
* To whom correspondence should be addressed. Tel: +44 1173313106; Email: l.wong{at}bristol.ac.uk
Received June 9, 2006; Accepted September 7, 2006
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 acid receptor ß2 (RARß2) promoted axonal regeneration in adult sensory neurones located peripherally. However, it is not known if RARß2 can promote axonal regeneration in cortical neurones of the CNS. Here, we demonstrate that delivery of RARß2 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 RARß2 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 RARß2-treated animals. These results suggest that a direct and selective delivery of RARß2 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present Address Department of Gene Therapy, Section of Infectious Diseases, Division of Medicine, Wright–Fleming Institute, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, UK.