Novel Small Molecule Therapeutic for Spinal Cord Injury

描述（由申请人提供）：据估计，脊髓损伤（SCI）的年发病率（不包括在事故现场死亡的人员）约为每年11，000例。据估计，目前美国受SCI影响的患者人数为250- 300，000。目前，SCI患者面临终身监禁的极端病态。肝细胞生长因子（HGF），也称为散射因子（SF），已证实对脑、脊髓和外周神经中的神经元具有散射、增殖和保护作用，并具有作为治疗脑和SCI的新型治疗剂的显著潜力。HGF/SF样化合物的给药有望成为SCI临床治疗的新方法。然而，采用基于基因或蛋白质的制剂的治疗方式通常昂贵且难以施用。因此，采用天然生长和保护因子的小分子模拟物的治疗方法可能是此类疗法的有力替代方案。Angion Biomedica的主要研究重点是开发调节HGF/SF/Met信号传导以获得治疗优势的小分子。为此，我们已经鉴定了一种小分子Refanalin，其通过激活HGF/SF受体Met来重现HGF/SF的生物活性。我们的工作假设是，Refanalin作为一种神经保护剂，同时促进细胞增殖，轴突生长，并在设置SCI功能恢复。正如我们的进展报告中所描述的，给予这种HGF/SF的小分子模拟物代表了治疗SCI的高度创新的方法，具有显著的临床潜力。在体外，Refanalin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、上皮细胞和许旺细胞增殖，并防止细胞凋亡和坏死。在脊髓缺血的实验模型中，Refanalin改善了神经恢复并保持了神经元和灰质的完整性。重要的是，在一个良好描述的和临床相关的SCI模型中，Refanalin改善了神经行为评分，减少了神经元细胞死亡并增强了神经元再生。一项全面的药物非临床研究质量管理规范（GLP）监管研究表明，Refanalin急性全身给药安全且耐受性良好。美国国立卫生研究院（NIH）快速介入发展计划（Rapid Access to Interventional Development program）进行的瑞法那林长期（3个月）安全性研究正在进行中，初步结果非常令人鼓舞。这项转化研究的第二阶段申请旨在充分探索Refanalin在SCI中的治疗潜力。在对Refanalin进行剂量反应、治疗时间窗和给药方案研究后，将确定Refanalin在SCI临床相关模型中的疗效。成功完成拟议的研究将使研究新药申请提交给美国食品药品监督管理局FDA的临床研究与瑞法那林。该提案的主要焦点是开发调节SF/HGF/Met信号传导以获得治疗优势的小分子。我们的主要HGF/SF模拟物Refanalin通过激活HGF/SF受体来重现HGF/SF的生物活性，代表了治疗脊髓损伤的高度创新方法，具有显著的临床潜力。

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.