Preclinical Development of M10 as a Therapeutic Agent for Scleroderma

M10 作为硬皮病治疗剂的临床前开发

• 批准号: 10382679
• 负责人: GALINA S BOGATKEVICH
• 金额: $ 25.2万
• 依托单位: FIBROBIOLOGICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382679
• 关键词: Address; Affect; Amino Acids; Animal Model; Anti-Inflammatory Agents; Area Under Curve; Autoimmune; Biodistribution; Biological; Biological Response Modifier Therapy; Biotechnology; Bleomycin; Body Weight; Bronchoalveolar Lavage Fluid; C-terminal; Cause of Death; Cell physiology; Chemistry; Cicatrix; Clinical; Clinical Trials; Collagen; Complex; Connective Tissue Diseases; Data; Deposition; Development; Diagnosis; Disease; Dose; Drug Kinetics; Event; Exhibits; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Formulation; Functional disorder; Goals; Hematology; Histology; Human; Immunosuppressive Agents; Inflammation; Interstitial Lung Diseases; Kidney; Lead; Legal patent; Liver; Lung; MET gene; Maximum Tolerated Dose; Metabolism; Minority; Modeling; Morbidity - disease rate; Mus; Organ; Organ Weight; Pathologic; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Plasma; Play; Pre-Clinical Model; Preventive; Process; Production; Property; Proteins; Public Health; Pulmonary Fibrosis; Quantitative Evaluations; Receptor Protein-Tyrosine Kinases; Role; Scleroderma; Serum; Skin; Small Business Technology Transfer Research; Specificity; Spleen; Structure of parenchyma of lung; System; Systemic Scleroderma; TGF-beta type I receptor; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Visceral; Woman; Work; base; chemical synthesis; cytokine; drug candidate; good laboratory practice; immune activation; interest; interstitial; milligram; mortality; mouse model; novel; novel therapeutic intervention; peptide drug; preclinical development; preclinical evaluation; primary endpoint; pulmonary function; receptor; secondary endpoint; skin fibrosis; subcutaneous; success; tocilizumab; treatment strategy; vascular injury

Abstract Scleroderma (systemic sclerosis, SSc) is an autoimmune fibrotic disorder that affects multiple systems including the skin and visceral organs of the body. The leading cause of death in scleroderma patients is pulmonary dysfunction resulting from progressive interstitial lung fibrosis. Although immunosuppressive agents and other drugs such as nintedanib may stabilize lung function, long-term treatment is required, significant toxicity may occur, and many patients fail to respond to such therapies. Around 40% of scleroderma-associated interstitial lung disease (SSc-ILD) patients will die within 10 years of diagnosis; therefore, there is an urgent need for new therapeutic approaches that would be more effective and less toxic than current treatments. Small peptides are widely involved in multiple cellular events and play very important roles in various cell functions. Interest in peptides as potential drug candidates remains high. With advances in such fields as chemical synthesis and peptide formulation, peptide drugs - especially short synthetic and long-acting peptides - are quickly increasing in the global market. The advantages of small peptides as drugs include their high biological activity, high specificity, and low toxicity. FibroBiologics, LLC proposes to develop the novel peptide M10 as an efficacious antifibrotic therapeutic agent, with a lead indication for the treatment of patients who suffer from SSc-ILD. In Specific Aim 1, we will determine basic PK parameters, metabolism, biodistribution, and toxicity of M10 after subcutaneous administration in mice. In Specific Aim 2, we will define the efficacious dosing of M10 in two different animal models of SSc-ILD: bleomycin-induced therapeutic mouse model and FSP-driven TβR1CA mouse model. The successful completion of these two specific aims will provide important information about the feasibility of developing M10 as a novel antifibrotic therapeutic and will justify further studies focusing on gaining FDA clearance, scaling production, and a human clinical trial.

抽象的 硬皮病（系统性硬化症，SSc）是一种自身免疫性纤维化疾病，影响多种 系统包括身体的皮肤和内脏器官。导致死亡的主要原因 硬皮病患者是由于进行性间质性肺病导致的肺功能障碍 纤维化。尽管免疫抑制剂和其他药物（如尼达尼布）可能会稳定病情 肺功能，需要长期治疗，可能会出现明显的毒性反应，很多患者 对此类疗法没有反应。大约 40% 的硬皮病相关间质性肺 疾病（SSc-ILD）患者将在诊断后 10 年内死亡；因此，当务之急是 需要比目前更有效且毒性更低的新治疗方法 治疗。 小肽广泛参与多种细胞事件，在 各种细胞功能。人们对肽作为潜在候选药物的兴趣仍然很高。和 化学合成及肽制剂、肽药物等领域的进展 - 特别是短合成肽和长效肽 - 在全球市场上正在迅速增长。 小肽作为药物的优点包括生物活性高、特异性高、 且毒性低。 FibroBiologics, LLC 提议开发新型肽 M10 作为有效的抗纤维化药物 治疗剂，主要适应症为治疗 SSc-ILD 患者。 在具体目标 1 中，我们将确定基本 PK 参数、代谢、生物分布和 M10 小鼠皮下注射后的毒性。在具体目标 2 中，我们将定义 M10 在两种不同的 SSc-ILD 动物模型中的有效剂量：博来霉素诱导 治疗小鼠模型和FSP驱动的TβR1CA小鼠模型。顺利完成 这两个具体目标将为开发M10的可行性提供重要信息 作为一种新型抗纤维化治疗药物，将证明进一步研究的重点是获得 FDA 批准 清除、扩大生产和人体临床试验。