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（由申请人提供）：由细胞外基质蛋白（胶原蛋白）过剩引起的硬皮病或皮肤纤维化位于皮肤中，或多余的胶原蛋白可能聚集在肾脏、肺、胃肠道和心脏中。硬皮病每年在美国影响大约400，000人，并且根据研究，硬皮病在美国每年的直接和间接成本为15亿美元。Morcover是主要的成本负担，成本为8.19亿美元（占总成本的56%）。终身收入的现值损失了1.79亿美元，即每死亡30万美元。直接成本为4.62亿美元（32%）或每人每年4，731美元，表明成本分布在长期疾病持续期间。目前，没有已知的治愈方法，硬皮病的确切原因仍然未知。 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被常规使用，但仅表现出边际疗效。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-γ（IFN）是一种潜在的治疗硬皮病通过抑制胶原合成。其他研究表明，将肝细胞生长因子（HGF）基因转染到博来霉素处理的小鼠中可预防硬皮病和肺纤维化的发生。虽然HGF、IFN γ或其它细胞因子的施用具有治疗前景，但由于溶液中的不稳定性和成本过高的生产方案，存在与基因治疗、重组蛋白或肽治疗相关的几个缺点。Angion Biomedica Corp.已经鉴定出一种称为Ang 1170的小分子化合物，其在体外和体内均显示出抗纤维化作用。我们的初步数据表明，Ang 1170有可能在体外降低纤维化标志物的表达，并在体内降低肺纤维化。该研究项目旨在探索开发Ang 1170作为硬皮病治疗新方法的可能性。皮肤纤维化或硬皮病是由皮肤中细胞外基质蛋白过剩引起的疾病，或者它可能成为系统性的，在肾脏、肺、胃肠道和心脏中聚集过量的胶原蛋白。硬皮病每年影响美国约40万人。目前还没有治疗硬皮病的方法，确切的原因仍然未知。本申请的目的是在硬皮病的临床相关模型中评价一种先导小分子候选药物，以开发足够的数据来继续SBIR II期研究。