Targeting Rho to Stimulate Repair After Spinal Cord Injury

Growth inhibitory proteins block axon regeneration in the CNS. Many growth inhibitory proteins have been identified, and the Nogo66 receptor (NgR) binds the three major myelin-derived inhibitors. Many studies now indicate that NgR signals to the small GTPase Rho. Our studies have shown that Rho is an important intracellular target for overcoming growth inhibition and promoting axon regeneration after injury. The inactivation of the Rho signaling pathway promotes neurite outgrowth of primary neuronal cell cultures plated on growth inhibitory substrates. To inactivate Rho signaling, C3 transferase, C3-05 (Cethrin™; a more potent C3 transferase derivative), and Y-27632, an inhibitor of Rho kinase, have been tested. In vivo, we have documented the regeneration of transected axons after treatment with C3 transferase, C3-05, and Y-27632. C3 transferase and C3-05 have been tested in two animal models: microcrush lesion of the adult rat optic nerve and over-hemisection of adult mouse spinal cord. Treatment with C3-05 gave similar results to C3 transferase, except that the required doses were much lower. Animals treated with C3 transferase, C3-05, or Y-27632 after SCI all showed axon regeneration and impressive functional recovery. Inactivation of Rho to promote regeneration and functional recovery after SCI is simple, and our studies reveal the potential for a new, straightforward technique to promote axon regeneration.