Novel Rho Kinase Inhibitor for Systemic Sclerosis

项目描述（由申请人提供）：该项目的总体目标是开发一种新型Rho激酶抑制剂（TRX-101）作为硬皮病/系统性硬化症（SSc）的新疗法。SSc是一种病因不明的慢性疾病，其特征是严重且常进行性纤维化，影响皮肤，在某些情况下影响内脏器官。由于没有批准的抗纤维化药物用于SSc，目前的主要治疗方法是非选择性免疫抑制。环磷酰胺是进展性皮肤受累的主要治疗方法，在疾病的早期阶段有效，但在后期似乎没有益处。此外，非特异性免疫抑制药物与显著的发病率和死亡率相关。因此，迫切需要能够同时提供抗炎和抗纤维化作用的新方法。Rho激酶抑制剂如法舒地尔（在日本批准用于脑血管痉挛）已被证明对各种纤维化和炎症的临床前模型有效；然而Rho激酶抑制剂尚未在SSc中进行测试。与法舒地尔相比，TRX-101对Rho激酶具有更强的效力和特异性，因此它有可能成为一种更有效的治疗方法，能够抑制SSc的纤维化和炎症过程。本研究有三个目的：1)评估口服TRX-101在小鼠体内的生物利用度、药代动力学和潜在毒性。2)观察TRX-101对体外培养的SSc患者皮肤成纤维细胞的抗纤维化作用。3)评价TRX-101对小鼠SSc模型的治疗效果。这些研究结果将为TRX-101作为SSc的新疗法的未来临床开发提供基础。由于其独特的作用机制和有效的抗纤维化和抗炎特性，该候选药物可能为SSc患者提供一种新的治疗选择，对失败的患者特别有益

DESCRIPTION (provided by applicant): The overall goal of this project is the preclinical development of a novel Rho kinase inhibitor (TRX-101) as a new therapy for scleroderma/systemic sclerosis (SSc). SSc is a chronic disease of unknown etiology characterized by severe and often progressive fibrosis affecting the skin and in some cases internal organs. Since there is no approved anti-fibrotic drug for SSc, the current mainstay of treatment has been non-selective immunosuppression. Cyclophosphamide is the main treatment for progressing skin involvement and is effective in early stages of the disease but does not appear to provide benefits at later stages. Furthermore, nonspecific immunosuppressive drugs are associated with significant morbidity and mortality. Hence, new approaches that may provide both anti-inflammatory and anti-fibrotic effects are urgently needed. Rho kinase inhibitors such as fasudil (approved in Japan for cerebral vasospasm) have proven effective in various preclinical models of fibrosis and inflammation; however Rho kinase inhibitors have not yet been tested in SSc. Because TRX-101 is much more potent and specific for Rho kinase as compared to fasudil, it has the potential to become a much more effective therapeutic capable of suppressing both fibrotic and inflammatory processes in SSc. There are three aims in this proposal: 1) Evaluate bioavailability, pharmacokinetics and potential toxicity o orally administered TRX-101 in mice. 2) Test the anti-fibrotic effects of TRX-101 on cultured skin fibroblasts derived from SSc patients. 3) Evaluate the therapeutic efficacy of TRX-101 in a mouse model of SSc. The results of these studies will provide the basis for future clinical development of TRX-101 as a novel therapy for SSc. Because of its unique mechanism of action and potent anti-fibrotic and anti-inflammatory properties, this drug candidate could provide SSc patients with a new therapeutic option of special benefit for patients that have failed the usual suboptimal immunosuppressive treatments.