Novel Rho Kinase Inhibitor for Systemic Sclerosis
治疗系统性硬化症的新型 Rho 激酶抑制剂
基本信息
- 批准号:8590747
- 负责人:
- 金额:$ 31.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-17 至 2015-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnti-Inflammatory AgentsAnti-inflammatoryAutoimmune ProcessBiological AvailabilityCerebrovascular SpasmChronic DiseaseClinicalCyclophosphamideDermalDevelopmentDiseaseDoseDrug KineticsEtiologyFibroblastsFibrosisFundingFutureGoalsGrantImmunosuppressionImmunosuppressive AgentsInflammationInflammatoryInflammatory ResponseInjuryInterstitial Lung DiseasesJapanModelingMorbidity - disease rateMusOrganPatientsPharmaceutical PreparationsPhasePre-Clinical ModelProcessPropertyResearchRho-associated kinaseSchemeSclerodermaSkinStagingSystemic SclerodermaTestingTherapeuticToxic effectToxicologyTreatment EfficacyWorkbasedrug candidatefasudilgraft vs host diseaseinsightkinase inhibitormortalitymouse modelnovelnovel strategiesnovel therapeuticspre-clinicalpublic health relevance
项目摘要
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.
描述(由申请人提供):该项目的总体目标是临床前开发一种新型 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,其特征是严重且经常进行性纤维化,影响皮肤,有时甚至影响内脏器官。由于尚无批准的治疗 SSc 的抗纤维化药物,目前的主要治疗方法是非选择性免疫抑制。环磷酰胺是治疗进行性皮肤受累的主要治疗方法,在疾病的早期阶段有效,但在后期阶段似乎没有效果。此外,非特异性免疫抑制药物与显着的发病率和死亡率相关。因此,迫切需要可以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(在日本被批准用于治疗脑血管痉挛)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。由于 TRX-101 与法舒地尔相比对 Rho 激酶更有效且更具特异性,因此它有可能成为一种更有效的治疗方法,能够抑制 SSc 中的纤维化和炎症过程。该提案有三个目标: 1) 评估小鼠口服 TRX-101 的生物利用度、药代动力学和潜在毒性。 2) 测试TRX-101对来自SSc患者的培养皮肤成纤维细胞的抗纤维化作用。 3) 评估 TRX-101 在 SSc 小鼠模型中的治疗效果。这些研究结果将为 TRX-101 作为 SSc 的新型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,该候选药物可以为 SSc 患者提供一种新的治疗选择,对失败的患者特别有益
通常的次优免疫抑制治疗。
项目成果
期刊论文数量(0)
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SUSAN C WRIGHT其他文献
SUSAN C WRIGHT的其他文献
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