Novel Therapy for Amyotrophic Lateral Sclerosis

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DESCRIPTION (provided by applicant): Literature indicates that HGF via its cytoprotective and tissue-regenerative activities protects a number of organs against traumatic and/or ischemic injury and fibrotic/degenerative disease. We have evaluated the effects of Refanalin/BB3 in preclinical models of ischemic stroke, hepatic, renal, pulmonary and myocardial ischemia-reperfusion injury including models of hepatic, renal and lung transplantation. Treatment with Refanalin/BB3 was associated with reduced mortality, improved organ function and preservation of tissue microarchitecture. These efficacy data (not presented here) and the efficacy of BB3/Rf to attenuate spinal cord injury and ischemic stroke as described in the preliminary results section, coupled with an excellent safety profile and ideal drugability characteristic, makes Refanalin/BB3 an ideal candidate for evaluation in other indications where HGF has shown efficacy, such as ALS. During our phase I grant period we have successfully confirmed that Refanalin prolongs survival of a commonly used mouse model of ALS. In addition, immunohistochemical analysis confirms the exciting result that Refanalin does indeed mimic the activities ascribed to HGF in this setting. We are excited to further investigate the efficacy of refanalin, and have independent verification of activity in our collaborators laboratory, with detailed mechanism of action studies; as various neuorotrophic factors have failed in the clinic, likely due in part to the extreme difficulty of adequately delivering such macromolecular, polypeptides, which will not cross the blood-brain barrier, to the CNS. Refanalin/BB3 will not have such limitations. PUBLIC HEALTH RELEVANCE: Recently HGF has demonstrated excellent efficacy in a mouse model of ALS. In this proposal, we are poised to continue our work to determine if our small molecule, HGF mimetic Refanalin will prove similarly efficacious. If so, at the end of this budget period we will be poised to bring Refanalin/BB3 to the clinic a potential therapeutic for Amyotrophic Lateral Sclerosis.