Lentiviral vector expressing retinoic acid receptor beta2 promotes recovery of function after corticospinal tract injury in the adult rat spinal cord.
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 beta2 (RARbeta2) promoted axonal regeneration in adult sensory neurones located peripherally. However, it is not known if RARbeta2 can promote axonal regeneration in cortical neurones of the CNS. Here, we demonstrate that delivery of RARbeta2 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 RARbeta2 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 RARbeta2-treated animals. These results suggest that a direct and selective delivery of RARbeta2 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.
Yip
Ping K
PK
Neurorestoration Group, Wolfson CARD, 2 MRC Centre for Developmental Biology, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK.
Wong
Liang-Fong
LF
Pattinson
Damian
D
Battaglia
Anna
A
Grist
John
J
Bradbury
Elizabeth J
EJ
Maden
Malcolm
M
McMahon
Stephen B
SB
Mazarakis
Nicholas D
ND
D000818:Animals; D001369:Axons / Q000502:physiology; D002469:Cell Separation; D002540:Cerebral Cortex; D015316:Genetic Therapy; D005822:Genetic Vectors; D004860:Infectious Anemia Virus, Equine / Q000235:genetics*; D008297:Male; D009044:Motor Cortex; D009416:Nerve Regeneration; D016501:Neurites / Q000502:physiology; D011712:Pyramidal Tracts / Q000166:cytology / Q000293:injuries* / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000502:physiology; D013119:Spinal Cord Injuries / Q000628:therapy*; D014161:Transduction, Genetic
D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta