Novel Restorative Therapy For Spinal Cord Injury

Li, Feng-Qiao

Abstract

This proposal responds to the solicitation of SBIR/STTR PHS 2006-2 for """"""""Develop new preclinical testing for promising therapies for acute and chronic central nervous system injury"""""""" by NINDS. Spinal cord injury (SCI) is a devastating traumatic CNS disorder confined about 200,000 Americans on wheelchairs, which two-thirds of the new victims are under the age of 30. Functional deficits following SCI result from damage to or severance of axons, loss of neurons and glia, and demyelination. SCI pathology is determined not only by the initial mechanical insult, but also by secondary processes including ischemia, free-radical formation, inflammation, and excitotoxicity. Currently, there is no cure for SCI, and methylprednisolone is the only choice on clinic, even without FDA approval. Clearly, novel therapies are urgently needed to maximally reduce the disastrous outcome and more effectively improve neurological functions. We have developed an anti-inflammatory/neuroprotective peptide, COG133 derived from the receptor-binding region of apolipoprotein E (apoE). Our intensive studies revealed that the small apoE-mimetic exerts significant bioactivities relevant to eliminate the secondary damage and foster the recovery of SCI in the following possible pathways: (1) anti-inflammation; (2) reducing excessive Ca2+ influx and protecting against excitotoxicity of glutamate; (3) reducing the production of free radical species and nitric oxide; (4) facilitate the removal of myelin debris, which may inhibit axonal regeneration; (5) promote the reconstruction of myelin sheath by delivering cholesterol and protecting oligodendrocytes; (6) promote axonal regeneration via neurotrophic effect. Our preliminary data showed that COG133 is neuroprotective in established murine models of multiple sclerosis and traumatic head injury, injurious conditions which share many common features with SCI. We hypothesize that COG133 may represent a new generation SCI therapeutic with the dual potentials of diminishing neurodegeneration of secondary damage and promoting axonal regeneration and remyelination. As a proof of concept, in this phase I proposal, we will use the murine contusion model of human SCI to test whether COG133 can improve behavioral outcome and pathological readout. The complete of this Phase I study will determine whether COG133 is a candidate therapy for SCI. Spinal cord injury (SCI) is a major devastating traumatic CNS disorder confined about 200,000 Americans on wheelchairs, which two-thirds of the new victims are under the age of 30. There is a critically unmet need for cure of SCI with the woeful fact that methylprednisolone is the only choice on clinic with suspicious effects. Now, we propose a small synthetic peptide derived from apolipoprotein E (apoE), namely COG133, as a promising therapeutic candidate for SCI. The design and synthesis of COG133 is based on our intensive studies on the neurobiological roles of apoE. Our pilot exploration indicates that COG133 may represent a neuroprotective effect through multiple mechanisms underlying the secondary damage after SCI and may also directly promote axonal regeneration and thus foster the functional recovery. We will test the potential neuroprotective effect in a mouse compression model of SCI first in this Phase I study. The complete of this proposal may validate whether COG133 is a promising therapy for SCI. ? ? ?