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

TY - JOUR

T1 - Lentiviral vector expressing retinoic acid 2 promotes recovery of function after corticospinal tract injury in the adult rat spinal cord

AU - Yip, Ping

AU - Wong, L-F

AU - Pattinson, D.

AU - Battaglia, Anna

AU - Grist, J.

AU - Bradbury, E.J.

AU - Maden, M.

AU - McMahon, S.B.

AU - Mazarakis, N.D.

PY - 2006/11/1

Y1 - 2006/11/1

N2 - 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 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.

AB - 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 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.

U2 - 10.1093/hmg/ddl251

DO - 10.1093/hmg/ddl251

M3 - Article

SN - 1460-2083

VL - 15

SP - 3107

EP - 3118

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 21

ER -