Anti-Fibrotic Therapy for Scleroderma/SSc

硬皮病/SSc 的抗纤维化治疗

基本信息

批准号：
7908258
负责人：
LATHA PAKA
金额：
$ 28.76万
依托单位：
ANGION BIOMEDICA CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7908258
关键词：
Adenosine Adrenal Cortex Hormones Adverse effects Affect Age Animal Model Animals Anti-Inflammatory Agents Antibodies Attenuated Autoimmune Diseases Autoimmune Process Bleomycin Blood Vessels Cicatrix Clinical Clinical Trials Collagen Connective Tissue Diseases Cyclophosphamide Data Dependence Deposition Dermal Development Disease Disease Progression Dose Enzymes Esophagus Evaluation Experimental Designs Extracellular Matrix Proteins Fibrosis Gastrointestinal tract structure Growth Factor Heart Histology Hydroxyproline Immunosuppressive Agents In Vitro Intestines Kidney Knock-out Lead Long-Term Effects Lung Measurement Measures Modeling Monitor Morbidity - disease rate Mus Oral Organ PDGFRA gene PDGFRB gene Patients Pharmaceutical Preparations Phase Plasma Platelet-Derived Growth Factor Pre-Clinical Model Pulmonary Fibrosis Punch Biopsy Quality of life Review Literature Route Scleroderma Skin Skin Tissue Small Business Innovation Research Grant Specimen Staging Staining method Stains Subcutaneous Injections Systemic Scleroderma Testing Therapeutic Thick Time Tissues Treatment Efficacy Trichrome stain Tyrosine Kinase Inhibitor United States Vascular Diseases Vascular Endothelial Growth Factors Vascular remodeling Wild Type Mouse Work adenosine deaminase base common treatment connective tissue growth factor cost design drug candidate expectation improved in vivo indium-bleomycin inhibitor/antagonist innovation mortality mouse model novel novel therapeutics pre-clinical prevent protein expression public health relevance pulmonary function receptor response small molecule symptom management treatment duration

项目摘要

DESCRIPTION (provided by applicant): Scleroderma (also known as systemic sclerosis-SSc) is an autoimmune disorder characterized primarily by progressive dermal and vascular fibrosis. Other organs are affected too, including lung, heart, esophagus, intestine, and kidney. Many patients who suffer from scleroderma/SSc also have a loss of pulmonary function. Scleroderma/SSc affects approximately 400,000 to 900,000 people in the United States every year. Mortality and morbidity in SSc are very high and are directly related to the extent of fibrosis in the involved organs. According to one study, the total cost attributed to scleroderma/SSc in the United States reached $1.5 billion annually. In this study, morbidity represented the major cost burden, associated with $820 million (56%) of the total costs. There is no known cure for scleroderma/SSc and the underlying cause remains unknown, though it is attributed to having an autoimmune component. Treatment is currently limited to management of symptoms in order to improve quality of life and limit long-term complications. Common treatments for scleroderma/SSc include immunosuppressive agents, anti-inflammatory agents, vasodilators and anti-fibrotic agents. Immunosuppressive agents such as corticosteroids and cyclophosphamide have demonstrated marginal efficacy, or have side effects. Therefore there is a critical need for effective and affordable therapeutic strategy. Increased expression of both platelet derived growth factor (PDGF) and its receptors (PDGFR1 and PDGFR2) have been demonstrated in skin of scleroderma patients. Furthermore, the possibility of PDGFR activation through auto-antibodies is a novel and provocative concept in autoimmune fibrotic diseases. Recent studies have indicated that another growth factor, vascular endothelial growth factor (VEGF), a potent angiogenic molecule, is over expressed in SSc patients. From an extensive review of the literature, we concluded that inhibiting both PDGFR and KDR (VEGFRII) may be an effective novel therapeutic strategy to benefit scleroderma/SSc patients. We identified a small molecule receptor tyrosine kinase inhibitor with activity against both PDGFR and KDR. We have characterized this molecule in vitro and in vivo and found that ANG-3154 displays significant inhibitory activity in animal models of scleroderma/SSc and lung fibrosis. Given these preliminary studies in combination with the potential clinical advantages of small molecule PDGFR/KDR inhibitors in the setting of scleroderma/SSc, the current SBIR Phase I application is designed to further characterize ANG-3154 in two preclinical animal models of scleroderma/SSc. PUBLIC HEALTH RELEVANCE: Scleroderma also known as systemic sclerosis (SSc) is a disease caused by a surplus of extracellular matrix protein localized in the skin, or it may become systemic with excess collagen collecting in the kidneys, lungs, gastrointestinal tract, and heart. Scleroderma affects approximately 400,000 to 990,000 people in the US every year. Mortality and morbidity in scleroderma/SSc are very high and are directly related to the extent of fibrosis in the involved organs. The exact cause remains unknown even though it is thought to be autoimmune disease and there is no known cure for scleroderma/SSc. The objective of this application is to evaluate a lead small- molecule drug candidate in two preclinical models of scleroderma/SSc to advance to SBIR Phase-II project with the ultimate objective of bringing our drug to clinical trials.

描述（由申请人提供）：硬皮病（也称为系统性硬化症-SSc）是一种自身免疫性疾病，主要特征为进行性真皮和血管纤维化。其他器官也会受到影响，包括肺、心脏、食道、肠和肾。许多患有硬皮病/SSc 的患者也会出现肺功能丧失。在美国，硬皮病/SSc 每年影响大约 400,000 至 900,000 人。 SSc 的死亡率和发病率非常高，并且与相关器官的纤维化程度直接相关。根据一项研究，在美国，硬皮病/SSc 造成的总费用每年达到 15 亿美元。在这项研究中，发病率是主要的成本负担，占总成本的 8.2 亿美元（56%）。硬皮病/SSc 尚无已知的治愈方法，其根本原因仍不清楚，但其归因于自身免疫成分。目前的治疗仅限于控制症状，以改善生活质量并限制长期并发症。硬皮病/SSc 的常见治疗包括免疫抑制剂、抗炎剂、血管扩张剂和抗纤维化剂。皮质类固醇和环磷酰胺等免疫抑制剂的疗效有限，或者有副作用。因此，迫切需要有效且负担得起的治疗策略。硬皮病患者皮肤中血小板衍生生长因子 (PDGF) 及其受体（PDGFR1 和 PDGFR2）的表达增加。此外，通过自身抗体激活 PDGFR 的可能性是自身免疫性纤维化疾病中一个新颖且具有争议性的概念。最近的研究表明，另一种生长因子血管内皮生长因子 (VEGF) 是一种有效的血管生成分子，在 SSc 患者中过度表达。通过对文献的广泛回顾，我们得出结论，抑制 PDGFR 和 KDR (VEGFRII) 可能是一种有益于硬皮病/SSc 患者的有效的新型治疗策略。我们鉴定出一种小分子受体酪氨酸激酶抑制剂，具有抗 PDGFR 和 KDR 活性。我们在体外和体内对该分子进行了表征，发现 ANG-3154 在硬皮病/SSc 和肺纤维化动物模型中表现出显着的抑制活性。鉴于这些初步研究结合小分子 PDGFR/KDR 抑制剂在硬皮病/SSc 中的潜在临床优势，当前的 SBIR I 期应用旨在进一步表征 ANG-3154 在两种硬皮病/SSc 临床前动物模型中的特征。公众健康相关性：硬皮病也称为系统性硬化症 (SSc)，是一种由皮肤局部细胞外基质蛋白过剩引起的疾病，或者由于过量的胶原蛋白聚集在肾脏、肺、胃肠道和心脏，该疾病可能会变成全身性疾病。在美国，硬皮病每年影响大约 400,000 至 990,000 人。硬皮病/SSc 的死亡率和发病率非常高，并且与相关器官的纤维化程度直接相关。尽管被认为是自身免疫性疾病，并且硬皮病/SSc 尚无已知的治疗方法，但确切原因仍不清楚。本申请的目的是在硬皮病/SSc 的两个临床前模型中评估主要的小分子候选药物，以推进 SBIR II 期项目，最终目标是将我们的药物纳入临床试验。