Safety & Suitability of Dabigatran to Inhibit Thrombin in Scleroderma

 描述(由申请人提供)：皮肤和肺纤维化导致硬皮病(系统性硬化症，SSC)的大量发病率。此外，导致肺纤维化的间质性肺病(ILD)是硬皮病患者死亡的主要原因。我们实验室和其他实验室的研究表明，凝血系统，尤其是丝氨酸蛋白酶凝血酶，与SSc-ILD的发病机制有关。凝血酶可以将正常的肺成纤维细胞转化为硬皮病成纤维细胞表型(例如，具有高收缩和高胶原合成的肌成纤维细胞特征)。Dabigatran etexilate是一种选择性凝血酶抑制剂，FDA批准用于预防心房颤动患者的血栓栓塞症并发症。它的作用方式与华法林不同，另一种抗凝剂已被证明对特发性肺纤维化(IPF)无效。我们有强大的临床前体外和动物数据表明，达比卡特兰依塞利特对凝血酶的抑制作用 在不干扰止血的剂量下改善肺纤维化。我们以及肺纤维化领域的其他专家认为，达比加特兰依昔洛韦作为一种潜在的治疗药物需要研究。 治疗SSc-ILD和IPF的抗纤维化药物。这是迈向第3期随机对照试验的必要的第一步，该提案的主要目的是确定达比卡特兰在SSC-ILD患者中的安全性。我们还将对达比加兰对皮肤和肺的潜在影响进行探索性研究，包括对血浆和支气管肺泡灌洗液中凝血酶生物活性的影响，以及对SSC皮肤和肺成纤维细胞生物学行为的影响。我们的长期目标是确定我们的基本结果是否将转化为对SSc-ILD的潜在临床干预，这可以在未来的随机对照试验中进行测试。这项建议解决了开发疾病修正药物的基本需要，以及目前缺乏安全有效的抗纤维化药物治疗SSC的问题，这两种药物在治疗这种往往是致命的疾病方面都是重大的未得到满足的需求。

 DESCRIPTION (provided by applicant): Skin and pulmonary fibrosis result in substantial morbidity in scleroderma (systemic sclerosis, SSc). Furthermore, interstitial lung disease (ILD) culminating in pulmonary fibrosis is a major cause of death among scleroderma patients. Studies from our laboratory and others implicate the coagulation system, most notably the serine protease thrombin, in the pathogenesis of SSc-ILD. Thrombin can transform normal lung fibroblasts to a scleroderma fibroblast phenotype (e.g., myofibroblast features with high contractility and high collagen synthesis). Dabigatran etexilate is a selective thrombin inhibitor which is FDA-approved for the prevention of thromboembolic complications in patients with atrial fibrillation. Its mode of action differs from that of warfarin, a different anticoagulant tht has been shown not to be effective in treating idiopathic pulmonary fibrosis (IPF). We have strong preclinical in vitro and animal data demonstrating that thrombin inhibition by dabigatran etexilate ameliorates lung fibrosis at doses that do not perturb hemostasis. We, as well as other experts in the field of lung fibrosis, believe that dabigatran etexilate needs to be studied as a potential anti-fibrotic agent for the treatment of SSc-ILD and IPF. A necessary first step toward a phase 3 RCT and the primary aim of this proposal is to establish the safety of dabigatran in SSc-ILD patients. We will also conduct exploratory studies of the potential effects of dabigatran on the skin and lungs, including effects on the biological activity of thrombin in plasma and bronchoalveolar lavage fluid, as well as on the biologic behavior of SSc skin and lung fibroblasts. Our long-term goal is to determine whether or not our fundamental results will translate to a potential clinical intervention for SSc-ILD which can be tested in a future randomized control trial. This proposal addresses the essential need to develop disease modifying drugs and the current lack of safe and effective anti-fibrotic drugs for SSc, both of which are significant unmet needs in the treatment of this often fatal disease.