Novel Therapeutic for Amyotrophic Lateral Sclerosis (ALS)

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/退行性疾病的伤害。我们评价了BB3/RF在缺血性卒中、肝、肾、肺和心肌缺血再灌注损伤的临床前模型中的作用，包括肝、肾和肺移植的模型。BB3/RF治疗与降低死亡率、改善器官功能和保存组织微结构有关。这些疗效数据(此处未列出)和初步结果部分中描述的BB3/RF减轻脊髓损伤的有效性，再加上出色的安全性和理想的药物能力特性，使BB3/RF成为评估HGF已显示疗效的其他适应症(如ALS)的理想候选者。我们处于独特的地位，可以在ALS的环境中测试小分子HGF模拟物，在ALS中，各种营养因子在临床上都失败了，部分原因可能是由于将这种无法跨越血脑屏障的大分子多肽充分输送到中枢神经系统的极端困难。BB3/RF不会有这样的限制。公共卫生相关性：最近，肝细胞生长因子在ALS小鼠模型中显示出极好的疗效。在这项提案中，我们准备确定我们的小分子HGF模拟BB3/RF是否会被证明同样有效。如果是这样的话，进一步的研究可能会将BB3/RF带入临床，作为ALS的一种可能的治疗方法，ALS是一种毁灭性的疾病，具有重大的未得到满足的医疗需求。

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 BB3/Rf in preclinical models of ischemic stroke, hepatic, renal, pulmonary and myocardial ischemia-reperfusion injury including models of hepatic, renal and lung transplantation. Treatment with BB3/Rf 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 as described in the preliminary results section, coupled with an excellent safety profile and ideal drug ability characteristic makes BB3/RF an ideal candidate for evaluation in other indications where HGF has shown efficacy, such as ALS. We are in the unique position to test out small molecular weight HGF mimetic in the setting of ALS, where various nueorotrophic 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. BB3/RF 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 determine if our small molecule, HGF mimetic BB3/Rf will prove similarly efficacious. If so, further studies could bring BB3/RF to the clinic as a possible therapy for ALS, a devastating disease with significant unmet medical need.