Assessment of NOVO-118 as a regenerative therapeutic in acute spinal cord injury

Project Summary The purpose of this proposal is to conduct a rigorous in vivo efficacy study to test the activity of our optimized lead moleculeNOVOin an animal model of spinal cord injurySCISCI prevalence ranges betweencases per million worldwideand is characterized by a catastrophic and irreversible loss of motor and sensory function below the level of injuryCurrentlyno treatments exist to address the fundamental cause of dysfunctionwhich is the disruption of neuronal connectivity and failed restoration of neuronal pathways after damageWe have discovered that low density lipoprotein receptor related proteinLRPis a novel master regulator of the diverse signaling pathways that converge onto the pathological hyperactivation of RhoAwhich is the necessary and sufficient signal for neuroregenerative failureIn animal modelsdirectly targeting RhoAor its downstream effector Rho associated kinaseROCKhas been well validated as a means of restoring neuronal regeneration and functional recovery after SCIHowevercurrent approaches which target the RhoA ROCK pathway do not discriminate between the pathological hyperactivation responsible for regenerative arrest and endogenous Rho activitywhich is needed for normal cellular functionIn targeting LRPwe have demonstrated that we can overcome pathological hyperactivation of RhoA while leaving endogenous function intactgreatly reducing the potential of toxicity via our approachTo this endwe have shown that both pharmacologic antagonism and genetic silencing of LRPresults not only in abrogation of pathological RhoA activitybut also coincides with a robust restoration of neuronal growth in the presence of a diverse array of inhibitory moleculesTo therapeutically target LRPin SCIwe have developed a novel biologic antagonist of LRPNOVOto be used as a therapeutic to promote neuronal regenerationIn this applicationwe look to assess the ability of NOVOto restore behavioral deficits after SCI in a long term in vivo model of SCISuccessful demonstration of the long term in vivo efficacy of NOVOwill warrant formal pre clinical development of our lead molecule for the treatment of SCIProject Narrative There are approximatelynew cases of spinal cord injurySCIeach year in the United States and yet there are no clinically available treatments capable of restoring the regenerative capacity of neurons in the central nervous system after injuryWe have shown that targeting LRPusing a biologic antagonist is able to block the receptor mediating a major cause of neuroregenerative failure and that blocking LRPresults in attenuation of the signaling that leads to regenerative arrest in damaged neuronsThe goal of this work is to demonstrate in vivo efficacy in a rigorouslong term animal model of SCI by demonstrating significant behavioral improvement after treatment with our drug