Novel Therapeutic for Amyotrophic Lateral Sclerosis (ALS)

肌萎缩侧索硬化症 (ALS) 的新疗法

• 批准号: 7537497
• 负责人: David E Smith
• 金额: $ 18.4万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537497
• 关键词: Amyotrophic Lateral Sclerosis; Animals; Astrocytes; Astrocytosis; Attenuated; Blood - brain barrier anatomy; Body Weight; Brain Stem; CCL2 gene; Caspase-1; Cessation of life; Characteristics; Clinic; Coculture Techniques; Coupled; Daily; Data; Degenerative Disorder; Disease; Documentation; Dose; Evaluation; Glial Fibrillary Acidic Protein; Hepatic; Histology; Hour; Immunoblotting; In Vitro; Injection of therapeutic agent; Injury; Ischemic Stroke; Kidney; Laboratories; Literature; Lung; Lung Transplantation; Maintenance; Measures; Medical; Modeling; Molecular Weight; Morphology; Motor Neurons; Mus; Myocardial Ischemia; Nervous System Physiology; Neurologic; Neurology; Numbers; Onset of illness; Organ; Pharmaceutical Preparations; Phosphorylation; Positioning Attribute; Pre-Clinical Model; Public Health; Rattus; Reperfusion Injury; Reporting; Safety; Spinal Cord; Spinal cord injury; Staging; Symptoms; System; Testing; Tissue Preservation; Tissues; Transgenes; Transgenic Organisms; Universities; Week; caspase-3; cell type; day; immunocytochemistry; improved; in vitro Model; in vivo; mimetics; mortality; mouse model; mutant mouse model; novel therapeutics; polypeptide; receptor; small molecule

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.

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。我们评估了BB 3/Rf在缺血性中风、肝脏、肾脏、肺和心肌缺血再灌注损伤的临床前模型（包括肝脏、肾脏和肺移植模型）中的作用。BB 3/Rf治疗与死亡率降低、器官功能改善和组织微结构保护相关。这些有效性数据（此处未列出）和BB 3/Rf减轻脊髓损伤的有效性（如初步结果部分所述），加上出色的安全性特征和理想的药物能力特征，使BB 3/RF成为评估HGF已显示有效性的其他适应症（如ALS）的理想候选药物。我们处于独特的位置，以测试出小分子量HGF模拟物在ALS的设置，其中各种营养因子在临床上失败，可能部分是由于充分递送这种大分子多肽的极端困难，其不会穿过血脑屏障，到CNS。BB 3/RF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，我们准备确定我们的小分子HGF模拟物BB 3/Rf是否会证明同样有效。如果是这样的话，进一步的研究可以将BB 3/RF作为ALS的可能疗法带到临床，ALS是一种严重未满足医疗需求的毁灭性疾病。