Abstract

One of the many reactive events that occurs following spinal cord injury (SCI) is the formation of a glial scar that surrounds the injury site. The glial scar is thought to be an inhibitory barrier to the regrowth of injured spinal axons due to the presence of growth inhibitory molecules. Chondroitin sulfate proteoglycans (CSPGs) are one of the main classes of inhibitory molecules that are present in the extracellular matrix of the glial scar, and are dramatically up-regulated after SCI . The bacterial enzyme chondroitinase ABC (ChABC) removes CSPG glycosaminoglycans, rendering the SCI environment more permissive to growth, and is a promising treatment option for SCI . However, despite the reported beneficial effects of ChABC treatment, the potential for achieving long term efficacy in traumatic injuries that mimic a human SCI has not yet been realised. Recently, a bacterial chondroitinase cDNA has been engineered to allow the expression and secretion of active chondroitinase enzyme by mammalian cells. Gene delivery of ChABC may have a number of advantages compared to previous treatment paradigms, including sustained delivery by spinal cord cells at the site of injury. We have assessed the efficacy of gene delivery of ChABC in a clinically relevant animal model of spinal contusion injury, which represents the most common form of SCI in humans. We delivered genetically modified ChABC via a lentiviral vector (LV-ChABC) to adult rats following T10 spinal contusion and have examined changes in spinal injury pathology and functional outcome. LV-ChABC resulted in sustained and widespread CSPG degradation in the contused rat spinal cord and this was associated with significantly reduced cavitation, enhanced neuronal survival and sparing of spinal axons, increased vascularisation throughout the injury site and a marked change in the nature of reactive gliosis and the inflammatory response around the injury epicenter and cavity borders. We also describe the effects of LV-ChABC on improving spinal conduction and behavioural function. These findings identify gene delivery targeting extracellular matrix as a promising strategy for repair following spinal cord injury.