The purpose of this proposal is to conduct a rigorous in vivo efficacy study to test the activity of our optimized lead molecule, NOVO-118, in an animal model of spinal cord injury (SCI). SCI prevalence ranges between 205-906 cases per million worldwide, and is characterized by a catastrophic and irreversible loss of motor and sensory function below the level of injury. Currently, no treatments exist to address the fundamental cause of dysfunction, which is the disruption of neuronal connectivity and failed restoration of neuronal pathways after damage. We have discovered that low-density lipoprotein receptor-related protein 1 (LRP1) is a novel master regulator of the diverse signaling pathways that converge onto the pathological hyperactivation of RhoA, which is the necessary and sufficient signal for neuroregenerative failure. In animal models, directly targeting RhoA, or its downstream effector Rho-associated kinase (ROCK), has been well-validated as a means of restoring neuronal regeneration and functional recovery after SCI. However, current approaches which target the RhoA/ROCK pathway do not discriminate between the pathological hyperactivation responsible for regenerative arrest and endogenous Rho activity, which is needed for normal cellular function. In targeting LRP1, we have demonstrated that we can overcome pathological hyperactivation of RhoA while leaving endogenous function intact, greatly reducing the potential of toxicity via our approach. To this end, we have shown that both pharmacologic antagonism and genetic silencing of LRP1 results not only in abrogation of pathological RhoA activity, but also coincides with a robust restoration of neuronal growth in the presence of a diverse array of inhibitory molecules. To therapeutically target LRP1 in SCI, we have developed a novel biologic antagonist of LRP1, NOVO-118, to be used as a therapeutic to promote neuronal regeneration. In this application, we look to assess the ability of NOVO-118 to restore behavioral deficits after SCI in a long-term in vivo model of SCI. Successful demonstration of the long-term in vivo efficacy of NOVO-118 will warrant formal pre-clinical development of our lead molecule for the treatment of SCI.
Public Health Relevance Statement: 8. Project Narrative There are approximately 20,000 new cases of spinal cord injury (SCI) each 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 injury. We have shown that targeting LRP1 using a biologic antagonist is able to block the receptor mediating a major cause of neuroregenerative failure and that blocking LRP1 results in attenuation of the signaling that leads to regenerative arrest in damaged neurons. The goal of this work is to demonstrate in vivo efficacy in a rigorous, long-term animal model of SCI by demonstrating significant behavioral improvement after treatment with our drug.
NIH Spending Category: Injury (total) Accidents/Adverse Effects; Injury - Trauma - (Head and Spine); Neurosciences; Regenerative Medicine; Spinal Cord Injury
Project Terms: Acute; Address; Aftercare; Anatomy; Animal Model; attenuation; axon growth; axon regeneration; Behavior; Behavioral; Biological; Biological Assay; Catheters; Cell physiology; Cells; Chest; Chronic; Cicatrix; Clinical; clinically relevant; Contusions; Dose; efficacy study; Event; Failure; Functional disorder; Genetic; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Heat shock proteins; Histopathology; improved; In Vitro; in vitro Model; in vivo; in vivo Model; Inflammation; Infusion procedures; Infusion Pumps; inhibitor/antagonist; Injury; LDL-Receptor Related Protein 1; Lead; lead optimization; Lesion; Ligation; Lipoprotein Receptor; Mediating; Modeling; Molecular Chaperones; Monitor; Monomeric GTP-Binding Proteins; Motor; Mus; Myelin; Myelin Associated Glycoprotein; Myelin Proteins; Natural regeneration; Nerve Regeneration; Nervous System Trauma; Neuraxis; Neurites; neuronal growth; Neurons; novel; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacology; preclinical development; premature; Prevalence; Process; programs; Proteins; Pump; Rattus; receptor; Recovery of Function; regenerative; regenerative therapy; remyelination; Research; response; restoration; rho; Rho-associated kinase; screening; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Solubility; Spinal Cord Contusions; Spinal cord injury; Stress; Structure; System; Testing; Therapeutic; therapeutic lead compound; therapeutic target; Thoracic spinal cord structure; Time; Toxic effect; Transferase; Translating; Treatment Efficacy; United States; Work
