Anti-Fibrotic Therapy for Scleroderma/SSc

硬皮病/SSc 的抗纤维化治疗

• 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
• 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

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的患者也有肺功能丧失。硬皮病/SSc每年影响美国约400，000至900，000人。SSc的死亡率和发病率非常高，并且与受累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的总成本每年达到15亿美元。在这项研究中，发病率是主要的成本负担，与总成本的8.2亿美元（56%）相关。硬皮病/SSc没有已知的治愈方法，其根本原因仍然未知，尽管它归因于具有自身免疫成分。目前的治疗仅限于控制症状，以提高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。免疫抑制剂，如皮质类固醇和环磷酰胺已证明边际疗效，或有副作用。因此，迫切需要有效和负担得起的治疗策略。血小板衍生生长因子（PDGF）及其受体（PDGFR 1和PDGFR 2）的表达增加已被证明在硬皮病患者的皮肤。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的一个新的和挑衅性的概念。最近的研究表明，另一种生长因子，血管内皮生长因子（VEGF），一种有效的血管生成分子，在SSc患者中过度表达。从广泛的文献综述中，我们得出结论，抑制PDGFR和KDR（VEGFRII）可能是一种有效的新的治疗策略，使硬皮病/SSc患者受益。我们鉴定了一种对PDGFR和KDR都具有活性的小分子受体酪氨酸激酶抑制剂。我们已经在体外和体内表征了这种分子，并发现ANG-3154在硬皮病/SSc和肺纤维化的动物模型中显示出显著的抑制活性。鉴于这些初步研究结合小分子PDGFR/KDR抑制剂在硬皮病/SSc背景下的潜在临床优势，当前SBIR I期申请旨在进一步表征ANG-3154在硬皮病/SSc的两种临床前动物模型中的特征。 公共卫生关系：硬皮病也被称为系统性硬化症（SSc）是由位于皮肤中的细胞外基质蛋白过剩引起的疾病，或者它可能变得全身性，过量胶原蛋白聚集在肾脏、肺、胃肠道和心脏中。硬皮病每年影响美国约40万至99万人。硬皮病/SSc的死亡率和发病率非常高，与受累器官的纤维化程度直接相关。尽管它被认为是自身免疫性疾病，而且硬皮病/SSc尚无已知的治疗方法，但确切的原因仍然未知。本申请的目的是在硬皮病/SSc的两个临床前模型中评估一种领先的小分子候选药物，以推进SBIR II期项目，最终目标是将我们的药物用于临床试验。