Small Molecule Anti-Fibrotic Therapy for Scleroderma

硬皮病的小分子抗纤维化治疗

基本信息

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
项目类别：
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

项目摘要

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）：由于细胞外基质蛋白（胶原蛋白）过剩而引起的皮肤硬皮病或纤维化局限于皮肤，或者过量的胶原蛋白可能聚集在肾脏、肺、胃肠道和心脏中。硬皮病每年影响美国约 40 万人，根据研究，美国每年因硬皮病造成的直接和间接费用为 15 亿美元。发病率是主要的成本负担，占总成本的 8.19 亿美元（56%）。当前的终生收入价值损失了 1.79 亿美元，即每次死亡损失了 30 万美元。直接费用为 4.62 亿美元 (32%)，即每人每年 4,731 美元，这表明费用分摊到较长的疾病持续时间内。目前，硬皮病尚无已知的治疗方法，其确切原因仍不清楚。治疗选择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已被常规使用，但仅显示出有限的疗效。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) 通过抑制胶原蛋白合成而成为治疗硬皮病的潜在疗法。其他研究表明，将肝细胞生长因子（HGF）基因转染到博来霉素治疗的小鼠体内可预防硬皮病和肺纤维化的发展。虽然 HGF、IFN γ 或其他细胞因子施用具有治疗前景，但由于溶液不稳定和成本高昂的生产方案，基因治疗、重组蛋白或肽治疗存在一些缺点。 Angion Biomedica Corp. 已鉴定出一种名为 Ang1170 的小分子化合物，该化合物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，Ang1170 有可能在体外降低纤维化标志物的表达，并在体内减少肺纤维化。拟议的研究项目旨在探索开发 Ang1170 作为治疗硬皮病的新治疗方法的可能性。皮肤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，或者由于过量的胶原蛋白聚集在肾脏、肺、胃肠道和心脏中而可能成为全身性疾病。在美国，硬皮病每年影响大约 40 万人。硬皮病尚无已知的治疗方法，确切原因仍不清楚。本申请的目的是评估硬皮病临床相关模型中的主要小分子候选药物，以开发足够的数据来继续 SBIR II 期研究。