Novel Therapy for Amyotrophic Lateral Sclerosis

描述（由申请人提供）：文献表明，HGF通过其细胞保护和组织再生活性保护许多器官免受创伤性和/或缺血性损伤以及纤维化/退行性疾病。我们已经评估了Refanalin/BB 3在缺血性中风、肝、肾、肺和心肌缺血-再灌注损伤的临床前模型（包括肝、肾和肺移植模型）中的作用。Refanalin/BB 3治疗与死亡率降低、器官功能改善和组织微结构保护相关。这些疗效数据（此处未列出）和BB 3/Rf减轻脊髓损伤和缺血性卒中的疗效（如初步结果部分所述），加上优异的安全性特征和理想的可药性特征，使Refanalin/BB 3成为评估HGF已显示疗效的其他适应症（如ALS）的理想候选药物。在我们的第一阶段资助期间，我们已经成功地证实，Refanalin延长了常用的ALS小鼠模型的生存期。此外，免疫组织化学分析证实了令人兴奋的结果，即Refanalin确实模拟了这种情况下归因于HGF的活性。我们很高兴能进一步研究refanalin的疗效，并在我们的合作者实验室中进行独立的活性验证，并进行详细的作用机制研究;因为各种神经营养因子在临床上失败，可能部分原因是难以充分递送此类大分子多肽，这些多肽不会穿过血脑屏障，到达CNS。Refanalin/BB 3不会有这样的限制。 公共卫生相关性：最近，HGF在ALS小鼠模型中表现出优异的疗效。在这个提议中，我们准备继续我们的工作，以确定我们的小分子，HGF模拟物Refanalin是否会证明同样有效。如果是这样，在本预算期结束时，我们将准备将Refanalin/BB 3带到临床，成为肌萎缩侧索硬化症的潜在治疗药物。

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.