RAP as a therapeutic compound for neuronal regeneration after spinal cord injury

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DESCRIPTION (provided by applicant): RAP as a therapeutic compound for neuronal regeneration after spinal cord injury Novoron Bioscience Inc. RESEARCH & RELATED Other Project Information 7. Project Summary There are an estimated 12,000 to 20,000 new cases of spinal cord injury (SCI) each year and 1.28 million people in the United States are paralyzed in some form due to SCI. Currently, there are no clinically available treatments that target the degraded myelin, one of the causes of regenerative failure in the central nervous system (CNS) after SCI. LRP1 was recently identified as a novel receptor of myelin-associated inhibitors (MAIs), the components of degraded myelin responsible for regenerative failure. We have shown in vivo that infusion of the LRP1 antagonist RAP into the injured spinal cord results in attenuation of RhoA, the critical neuronal signal involved in extrinsically-mediated regenerative failure. Direct inhibition of RhoA has been shown to enhance neuronal regeneration after SCI in rodent models and a pan-Rho inhibitor has shown evidence of efficacy in humans in exploratory clinical trials. However, current therapeutics have so far been limited to single dose administration. In contrast, RAP has been demonstrated to be readily available to the CNS from the peripheral circulation therefore making it amenable to repeated administration over time giving it therapeutic advantages over current pan-RhoA inhibitors. As beneficial results have already been observed using direct infusion to the injury site, we first wish to assess whether peripheral administration of RAP has comparable beneficial effects on the signaling events associated with regenerative failure after SCI. To accomplish this, an intravenous administration protocol capable of resulting in sufficient levels of RAP in the CNS must first be established. We will then perform long term studies (8-week injury course) to assess histological regeneration of damaged neurons, as well as evaluate the behavioral benefits over time such as improved locomotion, increased paw utilization, and response to external stimuli in affected extremities. We will also evaluate the effects of RAP infusion on immune infiltration and lesion formation. As LRP1 has been shown to be a critical facilitator of myelin mediated neuroregenerative failure, we hypothesize that therapeutic application of RAP to block the LRP1/MAI interaction will result in significant neuronal regeneration after SCI. Additionally, the unique biological characteristics of RAP such as CNS bioavailability could make it a superior, or perhaps combinatorial, therapeutic approach to the current pan-RhoA inhibitors. As such, RAP appears to be a high-value potential therapeutic for restoring function after acute spinal cord injury. This technology s protected by US patent pending (US2012/035125), which is currently in process of exclusive license to Novoron Inc. from the University of California San Diego.