The Development of CSD peptides for the therapeutic treatment of post-acute sequelae of COVID-19 (PACS)

摘要 SARS-CoV-2感染引起的急性呼吸窘迫综合征(ARDS)激活多个肺 特发性肺纤维化(IPF)中观察到的重塑途径和报道 约33%的住院患者症状持续2至12个月或更长时间 病人。为了解决这一新出现的健康问题，这项提案旨在1)制定一项 急性新冠肺炎后遗症器官纤维化模型的建立及意义 使用这个模型来严格评估一种潜在的预防性、抗纤维化药物的疗效 由肺治疗公司(LTI)申请专利并开发的治疗多肽。减少了 在人的纤维组织中观察到小窝蛋白-1的表达，组织病理学显示 10例独特致死性COVID患者内源性CAV-1蛋白表达显著降低 肺部。此外，CAV-1RNA在PAC组织样本中被减少，这些细胞用于 这个模型将会被推导出来。LTI专利产品Caveolin-1的抗纤维化活性 支架结构域(CSD)的多肽是通过7个氨基酸序列赋予的 FTTFTVT。 7-mer是一种吸入型干粉，目前正在进行一种 第1阶段安全性、耐受性和药代动力学研究(NCT04233814) 逆转多种体内临床前真皮模型中已建立的纤维化的能力， 心、肺纤维化(PF)并减轻多种促纤维化信号通路 在试管中。然而，鉴于在这项试验中观察到的剂量限制为20毫克，并且PACS已经 已观察到影响肺以外的其他器官以及全身血管系统， 更易溶，更稳定，XR，皮下，注射版本的LTI-03，称为LTI-2355。LTI- 2355在多种人体中显示出强大的抗炎和抗纤维化作用。 和啮齿动物纤维化模型。此外，我们仓库的初步PK数据，延期发布 (XR)制剂表明，单次注射后，它在肺中稳定并可用 推定的治疗剂量水平为14至22天。鉴于我们在IPF方面的经验- SCID小鼠系统，我们假设强健的肺纤维化可能发生 静脉注射活体人肺可形成多器官纤维化 来自废弃的COVID肺移植(病毒滴度阴性)的细胞进入SCID小鼠。如果 成功建立，我们不仅将测试三个假定的缓释片(XR) 这个新的PACS模型中的治疗多肽，但我们也将发表这些方法和 模型的特征，这可能成为测试的重要工具 可能是PACS介入治疗学。综上所述，我们建议建立一个 PACS的翻译小鼠模型，并通过测试三种专利LTI-2355-XR配方 (SC)给药并与对照多肽和宁替达尼的疗效进行比较 IPF的护理，以及目前PACS治疗的候选者(Pincer，NCT04856111)。待定 有效结果(AT的促炎和促肝纤维化指标的综合减少 至少40%，将选择主要候选人，并将提交第二阶段SBIR以支持 进一步的临床发展(PK/PD，SC制剂的特定毒理学，IND支持 工作)。这一建议迎合了包括多肽在内的团队的总体实力 在翻译小鼠模型的生化评估方面的配方和专业知识 肺纤维化、免疫学、器官纤维化、药代动力学和整体药物 发展。最后，该项目有很强的潜力产生一种新的治疗方法。 在PACS系统中。

Abstract Acute respiratory distress syndrome (ARDS) from SARS-CoV-2 infection activates many lung remodeling pathways observed in Idiopathic Pulmonary Fibrosis (IPF) and reports indicate that symptoms persist for 2 to 12 months or longer in approximately 33% of hospitalized patients. To address this emerging health concern, this proposal aims to 1) develop a translational model for post-acute COVID-19 sequelae (PACS) induced organ fibrosis and to use this model to 2) rigorously assess efficacy of a potentially prophylactic, antifibrotic therapeutic peptides patented and developed by Lung Therapeutics, Inc (LTI). A reduction of Caveolin-1 expression is observed in human fibrotic tissues and histopathology revealed that endogenous CAV-1 protein expression was significantly reduced in 10 unique fatal COVID lungs. Furthermore, CAV-1 RNA was reduced in PACs tissue samples from which cells for this model will be derived. The anti-fibrotic activity of LTI’s patented portfolio of Caveolin-1 scaffolding domain (CSD) peptides is conferred through the 7-amino acid sequence FTTFTVT. The 7-mer was formulated as an inhaled dry powder and is currently undergoing a phase 1 safety, tolerability, and pharmacokinetic study (NCT04233814) as it demonstrated the ability to reverse established fibrosis in multiple in vivo pre-clinical models of dermal, cardiac, and pulmonary fibrosis (PF) and attenuates multiple pro-fibrotic signaling pathways in vitro. However, given that a dose limit of 20mg was observed in this trial, and PACS has been observed to effect other organs aside from the lung as well as systemic vasculature, a more soluble, stable, XR, subcutaneous, injectable version of LTI-03, called LTI-2355. LTI- 2355 has demonstrated robust anti-inflammatory and antifibrotic effects in a variety of human and rodent fibrosis models. Moreover, preliminary PK data on our depot, extended release (XR) formulations indicate that it is stable and available in the lung following a single injection at putative therapeutic dose levels out to 14 to 22 days. Given our experience with the IPF- SCID mouse system, we hypothesize that robust lung fibrosis with possible development of multi-organ fibrosis will develop following intravenous administration of live human pulmonary cells from discarded COVID lung transplants (viral titer negative) into SCID mice. If successfully established, we will not only test three putative extended-release (XR) therapeutic peptides in this novel PACS model, but we will also publish the methods and characteristics of the model, which may potentially become an important tool for testing putative PACS interventional therapeutics. Taken together, we propose to establish a translational mouse model of PACS, and to test three patented LTI-2355-XR formulations via (SC) delivery and compare against efficacy of a control peptide and Nintedanib, the standard of care for IPF, and a current candidate for PACS therapy (PINCER, NCT04856111). Pending efficacious results (composite reduction in pro-inflammatory and pro-fibrotic indicators of at least 40%, a lead candidate will be selected, and a Phase II SBIR will be filed to support further clinical development (PK/PD, toxicology specific to the SC formulation, IND-supporting work). This proposal caters to the aggregate strengths of the team including peptide formulation, expertise in the biochemical assessment of translational mouse models of pulmonary fibrosis, immunology, organ fibrosis, pharmacokinetics, and overall drug development. Finally, this project has strong potential to yield a novel therapy for the treatment of PACS.