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， 包括皮肤和身体内脏器官的系统。死亡的主要原因 硬皮病患者是由于进行性间质性肺 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 肺功能，需要长期治疗，可能会发生严重的毒性，许多患者 对这种疗法没有反应。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， 需要新的治疗方法，这将是更有效的和更少的毒性比目前的 治疗。 小分子肽广泛参与多种细胞事件，在细胞免疫中起着非常重要的作用。 各种细胞功能。对肽作为潜在候选药物的兴趣仍然很高。与 在化学合成和肽制剂、肽药物- 特别是短合成肽和长效肽-在全球市场上迅速增加。 小肽作为药物的优点包括其高生物活性，高特异性， 且毒性低。 FibroBiologics，LLC提出开发新型肽M10作为有效的抗纤维化药物。 治疗剂，主要适应症为SSc-ILD患者的治疗。 在具体目标1中，我们将确定基本PK参数、代谢、生物分布和 小鼠皮下给药后M10的毒性。在具体目标2中，我们将定义 M10在两种不同的SSc-ILD动物模型中的有效给药：博来霉素诱导 治疗性小鼠模型和FSP驱动的Tβ R1 CA小鼠模型。圆满完成 这两个具体的目标将提供有关发展M10的可行性的重要信息 作为一种新的抗纤维化治疗，并将证明进一步的研究重点是获得FDA 清除、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.