A Better Way to Excise Inhibitory Molecules (CSPGs) from a Spinal Cord Injury Scar to Promote Regeneration

Abstract : A major consequence of spinal cord injury (SCI) is the development of a glial scar. Although the scar has benefits for tissue repair, it also blocks neural regeneration. Inhibitory chondroitin sulfate proteoglycans (CSPGs) are elevated in the glial scar and are a major deterrent to successful regeneration. In the present study, we have demonstrated that injured astrocytes produce a wide variety of inhibitory CSPGs. To develop a more efficient method to accomplish CSPG degradation (than the bacterial enzyme chondroitinase), we are addressing a normally occurring catabolic protein for CSPG degradation, the neural aggrecanase, ADAMTS-4. We employed a two-prong approach, using studies both in vitro, and in vivo. We produced recombinant ADAMTS-4 protein and used this enzyme to reduce CSPG inhibition in experiments both in-vitro, and in vivo. We have developed critical reagents (lentivirus) and methods, and have tested these in proof of principle assays, as well as in a dorsal SCI in a rodent model. We are conducting behavioral assessments to validate the success of aggrecanase treatment, and have data indicating that aggrecanase successful ameliorates some of the negative consequences of dorsal SCI injury. The final stage of this study (no cost extension) will be to repeat the aggrecanase tests, combining it with chondroitinase ABC. The significance of these studies is the development of an efficient means by which to attenuate axonal inhibition, and thereby promote plasticity and regeneration of adult neurons following SCI.