Novel Small Molecule Therapeutic for Spinal Cord Injury

描述（由申请人提供）：据估计，不包括在事故现场死亡的人，脊髓损伤（SCI）的年发病率约为每年11,000例。目前美国脊髓损伤患者的数量估计在250-30万之间。目前，脊髓损伤患者面临着终身极高的发病率。肝细胞生长因子（HGF），也被称为散点因子（SF），已被证明对脑、脊髓和周围神经的神经元具有散射、增殖和保护作用，并且具有作为脑和脊髓损伤治疗的新药物的巨大潜力。给药HGF/ sf样化合物有望成为脊髓损伤临床治疗的新方法。然而，采用基于基因或蛋白质的配方的治疗方式具有昂贵和难以实施的特点。因此，采用自然生长和保护因子的小分子模拟物的治疗方法可能是这种疗法的有力替代品。Angion Biomedica的主要研究重点是开发调节HGF/SF/Met信号传导的小分子，以获得治疗优势。为此，我们已经确定了一个小分子，Refanalin，它通过激活HGF/SF受体Met来概括HGF/SF的生物活性。我们的工作假设是，在脊髓损伤的情况下，Refanalin作为一种神经保护剂，同时促进细胞增殖、轴突生长和功能恢复。正如我们的进展报告所述，这种小分子HGF/SF模拟物的给药代表了一种高度创新的治疗SCI的方法，具有显著的临床潜力。在体外，reanalin激活与HGF/SF相同的细胞内信号级联，分散肾细胞，诱导内皮细胞、上皮细胞和雪旺细胞增殖，并防止凋亡和坏死细胞死亡。在脊髓缺血的实验模型中，reanalin促进神经恢复并保持神经元和灰质的完整性。重要的是，在一个描述良好且与临床相关的脊髓损伤模型中，reanalin可改善神经行为评分，减轻神经元细胞死亡并增强神经元再生。一项全面和良好的实验室规范的研究表明，急性全身给药雷伐那林是安全的，耐受性良好。由美国国立卫生研究院（NIH）介入发展快速获取项目进行的reanalin的长期（3个月）安全性研究正在进行中，初步结果非常令人鼓舞。这项转化研究II期申请旨在充分探索Refanalin在脊髓损伤中的治疗潜力。随后将进行Refanalin的剂量反应、治疗时间窗和给药计划研究，以确定Refanalin在SCI临床相关模型中的疗效。拟议研究的成功完成将使reanalin的临床研究向美国食品和药物管理局（FDA）提交新药研究申请。本提案的主要重点是开发调节SF/HGF/Met信号传导的小分子以获得治疗优势。我们的主要HGF/SF模拟物reanalin通过激活HGF/SF受体来重现HGF/SF的生物活性，代表了一种高度创新的脊髓损伤治疗方法，具有重要的临床潜力。

DESCRIPTION (provided by applicant): It is estimated that the annual incidence of spinal cord injury (SCI), not including persons who die at the scene of the accident, is approximately 11,000 cases per year. The number of patients currently affected by SCI in the United States has been estimated at 250-300,000. Currently patients with SCI face a life-long sentence of extreme morbidity. Hepatocyte growth factor (HGF), also known as Scatter factor (SF), has documented scattering, proliferating, and protective effects on neurons in the brain, spinal cord, and in peripheral nerves, and has significant potential as a novel therapeutic agent for the treatment of brain and SCI. Administration of an HGF/SF-like compound holds promise as a new approach to the clinical management of SCI. However, treatment modalities that employ gene- or protein-based formulations are characteristically expensive and difficult to administer. Therefore, therapeutic approaches that employ small molecule mimetics of natural growth and protective factors may be powerful alternatives to such therapies. The primary focus of research at Angion Biomedica is the development of small molecules that regulate HGF/SF/Met signaling to therapeutic advantage. To this end, we have identified a small molecule, Refanalin, that recapitulates the biologic activity of HGF/SF by activating the HGF/SF receptor, Met. Our working hypothesis is that Refanalin acts as a neuroprotectant while promoting cell proliferation, axonal growth, and functional recovery in the setting of SCI. As delineated in our Progress Report, administration of this small molecule mimetic of HGF/SF represents a highly innovative approach for the treatment of SCI, with significant clinical potential. In vitro, Refanalin activates the same intracellular signaling cascades as HGF/SF, scatters renal cells, induces endothelial, epithelial and Schwann cell proliferation, and protects against apoptotic and necrotic cell death. In an experimental model of spinal cord ischemia, Refanalin improves neurological recovery and preserves neuronal and grey matter integrity. Importantly, in a well-described and clinically relevant model of SCI, Refanalin improves neurobehavioral score, attenuates neuronal cell death and augments neuronal regeneration. A comprehensive and good laboratory practice adherent set of regulatory studies indicates that acute systemic administration of Refanalin is safe and well- tolerated. Long-term (3-month) safety studies of Refanalin undertaken by the National Institutes of Health NIH Rapid Access to Interventional Development program are underway and preliminary results are extremely encouraging. This translational research Phase II application is designed to explore fully the therapeutic potential of Refanalin in SCI. Dose-response, treatment time window and dosing schedule studies for Refanalin will be followed by determination of Refanalin efficacy in clinically relevant models of SCI. Successful completion of the proposed research will enable submission of an Investigational New Drug Application to Food and Drug Administration FDA for clinical studies with Refanalin. The primary focus of this proposal is the development of small molecules that regulate SF/HGF/Met signaling to therapeutic advantage. Our lead HGF/SF mimetic, Refanalin recapitulates the biologic activity of HGF/SF by activating the HGF/SF receptor, and represents a highly innovative approach to the treatment of spinal cord injures, with significant clinical potential.