Preclinical Development of M10 as a Therapeutic Agent for Scleroderma

摘要 硬皮病(系统性硬化症，SSC)是一种自身免疫性纤维化疾病，影响多发性 包括身体的皮肤和内脏器官的系统。年的主要死因是 硬皮病患者是进行性间质性肺功能障碍 纤维化症。尽管免疫抑制剂和其他药物，如9tedanib可能会稳定下来 肺功能不全，需要长期治疗，可能会出现明显的毒性反应，且患者多 对这种疗法没有反应。约40%的硬皮病相关间质肺 疾病(SSc-ILD)患者将在确诊后10年内死亡；因此，迫切需要 需要比目前更有效、毒性更低的新治疗方法 治疗。 小肽广泛参与多种细胞事件，在多种细胞事件中发挥重要作用。 各种细胞功能。人们对多肽作为潜在候选药物的兴趣仍然很高。使用 化学合成、多肽制剂、多肽药物等领域的研究进展 尤其是短合成和长效肽-在全球市场上正在迅速增加。 小肽作为药物的优点包括生物活性高，特异性强， 且毒性低。 FibroBiologics，LLC建议开发新型多肽M10作为有效的抗纤维化药物 治疗药物，具有治疗SSc-ILD患者的先导适应症。 在具体目标1中，我们将确定基本的PK参数、代谢、生物分布和 小鼠皮下注射M10的毒性。在具体目标2中，我们将定义 M10在博莱霉素诱导的两种不同SSC-ILD动物模型中的有效剂量 治疗性小鼠模型和FSP驱动的T-βR1CA小鼠模型。圆满完成 这两个具体目标将为开发M10的可行性提供重要信息 作为一种新的抗纤维化疗法，并将证明专注于获得FDA的进一步研究是合理的 批准、规模化生产和人体临床试验。

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.