Lentiviral vector expressing retinoic acid receptor β2 promotes recovery of function after corticospinal tract injury in the adult rat spinal cord

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 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.

Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors

“…This is mainly associated with the inability of neurons in the CNS to repair or regenerate their axons post-trauma. The use of viral vectors to express neurotrophic 22 or transcriptional factors 23 in the rubrospinal or corticospinal tracts, respectively, in SCI animal models has produced encouraging results. We have demonstrated efficient gene delivery to both corticospinal and rubrospinal tracts in rats using a VSVG pseudotyped NILV vector administered into the cerebral motor cortex or red nucleus, with approximately 20% transfection rate for the corticospinal, and under optimal conditions, more than 40% for the rubrospinal tract, respectively.…”

Lentivirus-mediated estrogen receptor α overexpression in the central nervous system ameliorates experimental autoimmune encephalomyelitis in mice

“…We introduced the recombinant lentivirus vectors via the administration of lateral cerebral ventricle injections. Compared to adenovirus, lentivirus has high transfection efficiency in non-dividing cells, a sustained expression potency and minimal impact on normal cellular functions (37)(38)(39). Previous studies have demonstrated the feasibility of the lentivirus-mediated delivery of ERα (26,40).…”

New Vectors for Stable and Safe Gene Modification

“…Although EIAV-based vectors are about 10-fold less efficient in several human cell lines than HIV-1 based vectors (Ikeda et al, 2002), they have demonstrated good efficiency for treatment of neuromuscular pathologies in animal models (Azzouz et al, 2004;Yip et al, 2006). In addition, they are able to transduce human HSCs (Siapati et al, 2005) and are very efficient in vivo.…”