Small Molecule Anti-Fibrotic Therapy for Scleroderma

硬皮病的小分子抗纤维化治疗

• 批准号: 7271474
• 负责人: LATHA PAKA
• 金额: $ 21.6万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-27 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271474
• 关键词: Actins; Adrenal Cortex Hormones; Affect; Age; Animal Model; Animals; Anti-Inflammatory Agents; Attenuated; Biological Availability; Bleomycin; Cells; Cessation of life; Clinical; Collagen; Collagen Diseases; Colorado; Condition; Connective Tissue; Connective Tissue Diseases; Daily; Data; Deposition; Dermal; Development; Direct Costs; Disease; Disease Progression; Dose; Etiology; Evaluation; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Facilities and Administrative Costs; Fibroblasts; Fibrosis; Gastrointestinal tract structure; Growth Factor Gene; Harvest; Health Sciences; Heart; Hepatocyte Growth Factor; Human; Hydroxyproline; Immunosuppressive Agents; In Vitro; Inflammation; Injection of therapeutic agent; Interferon Type II; Interstitial Collagenase; Kidney; Knowledge; Lead; Letters; Liver; Localized; Lung; Modeling; Molecular Weight; Morbidity - disease rate; Mus; Onset of illness; Oral; Pathogenesis; Pathway interactions; Patients; Peptides; Persons; Pharmaceutical Preparations; Phase II Clinical Trials; Philadelphia; Pilot Projects; Positioning Attribute; Pre-Clinical Model; Production; Proteins; Pulmonary Fibrosis; Quality of life; Rattus; Recombinant Proteins; Research Project Grants; Rheumatologic Disorder; Route; Safety; Scheme; Scleroderma; Score; Skin; Skin Tissue; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Solutions; Survival Rate; Symptoms; Therapeutic; Time; Tissue Sample; Tissues; Toxicology; Transfection; Treatment Efficacy; Trichrome stain; United States; Universities; Week; Western Blotting; Work; analog; base; clinically relevant; clinically significant; connective tissue growth factor; cost; cytokine; design; expectation; gene therapy; human TGFB1 protein; illness length; improved; in vivo; innovation; mimetics; mortality; mouse model; novel; novel therapeutics; prevent; protein expression; research study; small molecule; symptom management; therapeutic target; treatment duration

DESCRIPTION (provided by applicant): Scleroderma or fibrosis of skin caused by a surplus of extracellular matrix protein (collagen) is localized in the skin, or excess collagen may be collected in the kidneys, lungs, gastrointestinal tract, and heart. Scleroderma affects approximately 400,000 persons in the United States every year and according to research studies, annual direct and indirect costs of scleroderma in the United States are $1.5 billion. Morbidity represents the major cost burden, with costs of $819 million (56%) of total costs. The current value of lifetime earnings lost $179 million or $300,000 per death. Direct costs are $462 million (32%) or $4,731 per person annually, indicating that costs are spread over the long disease duration. Currently, there is no known cure and the exact cause remains unknown for scleroderma. Treatment options include, relieving or controlling symptoms. For example, corticosteroids and other immunosuppressive medications are being routinely employed, but have demonstrated only marginal efficacy. Hence there is a critical need for effective but affordable therapies. Recent studies have shown that Interferon-gamma (IFN) is a potential therapy for Scleroderma by inhibiting collagen synthesis. Other studies have shown that transfection of Hepatocyte growth factor (HGF) gene to the bleomycin treated mice prevented the development of Scleroderma and lung fibrosis. While HGF, IFN gamma or other cytokine administration holds therapeutic promise, there are several drawbacks associated with gene therapy, recombinant proteins, or peptide therapy because of instability in solution, and cost-prohibitive production schemes. Angion Biomedica Corp. has identified a small molecule compound, termed Ang1170 that showed antifibrotic effects both in vitro and in vivo. Our preliminary data indicate that Ang1170 has the potential to decrease the expression of fibrotic markers in vitro and decreased pulmonary fibrosis in vivo. The proposed research project is designed to explore the possibility of developing Ang1170 as a new therapeutic approach for the treatment of Scleroderma. Dermal Fibrosis or Scleroderma, 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 people in the United States every year. There is no known cure for Scleroderma and the exact cause remains unknown. The objective of this application is to evaluate a lead small-molecule drug candidate in clinically relevant models of Scleroderma to develop sufficient data to continue SBIR Phase II studies.

描述(申请人提供)：由细胞外基质蛋白(胶原)过剩引起的硬皮病或皮肤纤维化局限于皮肤，或多余的胶原可能聚集在肾脏、肺、胃肠道和心脏。硬皮病每年在美国影响大约40万人，根据研究，美国硬皮病每年的直接和间接成本为15亿美元。发病率是主要的费用负担，费用为8.19亿美元(占总费用的56%)。终身收入的现值损失了1.79亿美元，即每死一次损失30万美元。直接成本为4.62亿美元(32%)，或每人每年4731美元，这表明成本分散在长期患病期间。目前，硬皮病还没有已知的治疗方法，确切的原因还不清楚。治疗方案包括缓解或控制症状。例如，皮质类固醇和其他免疫抑制药物正在被常规使用，但仅显示出微乎其微的效果。因此，迫切需要有效但负担得起的疗法。最近的研究表明，干扰素是一种通过抑制胶原合成来治疗硬皮病的潜在药物。其他研究表明，将肝细胞生长因子(HGF)基因转导到博莱霉素治疗的小鼠可以防止硬皮病和肺纤维化的发展。虽然HGF、干扰素或其他细胞因子治疗有希望，但由于溶液不稳定和成本高昂的生产方案，与基因治疗、重组蛋白或多肽治疗相关的一些缺点。Angion Biomedica Corp.已经确定了一种名为Ang1170的小分子化合物，该化合物在体外和体内都显示出抗纤维化作用。我们的初步数据表明，Ang1170在体外有可能降低纤维化标志物的表达，在体内具有减轻肺纤维化的作用。拟议的研究项目旨在探索将Ang1170开发为治疗硬皮病的新治疗方法的可能性。真皮纤维化或硬皮病，是一种由皮肤中细胞外基质蛋白过剩引起的疾病，也可能成为全身性疾病，肾脏、肺、胃肠道和心脏中聚集了过量的胶原。在美国，硬皮病每年影响大约40万人。硬皮病目前还没有已知的治疗方法，确切的原因也尚不清楚。这项应用的目的是评估一种在硬皮病临床相关模型中的领先小分子候选药物，以开发足够的数据来继续SBIR第二阶段研究。