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

用于治疗 COVID-19 急性后遗症 (PACS) 的 CSD 肽的开发

• 批准号: 10602971
• 负责人: BreAnne MacKenzie
• 金额: $ 25.93万
• 依托单位: LUNG THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602971
• 关键词: Acute; Acute Respiratory Distress Syndrome; Address; Amino Acid Sequence; Animal Model; Anti-Inflammatory Agents; Attenuated; Biochemical; Biological Assay; Biological Availability; Bleomycin; Blood; COVID-19; COVID-19 patient; COVID-19/ARDS; Cell model; Cells; Characteristics; Clinical Trials; Data; Development; Dose; Dose Limiting; Drug Kinetics; Dryness; Fibrosis; Formulation; Foundations; Genetic Models; Goals; Harvest; Health; Heart; Histopathology; Hospitalization; Human; Hydroxyproline; Immunology; In Vitro; Infection; Inflammation; Inflammatory; Inhalation; Injectable; Injections; Injury; Kidney; Lead; Legal patent; Lung; Lung Transplantation; Methods; Modeling; Molecular Analysis; Mus; Nonspecific Interstitial Pneumonia; Operative Surgical Procedures; Organ; Organ Harvestings; Outcome; Pathway interactions; Patients; Peptides; Phase; Pilot Projects; Post-Acute Sequelae of SARS-CoV-2 Infection; Powder dose form; Pre-Clinical Model; Profibrotic signal; Public Health; Publishing; Pulmonary Fibrosis; RNA; Reporting; Research Contracts; Rodent; SARS-CoV-2 infection; SCID Mice; Safety; Signal Pathway; Slide; Small Business Innovation Research Grant; Symptoms; System; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Sample; Tissues; Toxicology; Trichrome stain; Viral; Work; attenuation; caveolin 1; cell type; clinical development; cohort; comparison control; coronary fibrosis; coronavirus disease; cytokine; drug development; efficacy evaluation; experience; high risk; hospital readmission; idiopathic pulmonary fibrosis; in vivo; injured; interstitial; intravenous administration; lead candidate; mouse model; nintedanib; novel; novel therapeutics; peptide drug; prophylactic; protein expression; pulmonary symptom; scaffold; skin fibrosis; standard of care; subcutaneous; synthetic polymer Bioplex; tool; translational model

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.

抽象的 SARS-COV-2感染的急性呼吸遇险综合征（ARDS）激活许多肺 在特发性肺纤维化（IPF）中观察到的重塑途径，并报告表明 该符号持续2到12个月或更长时间，大约33％的住院 患者。为了解决这一新出现的健康问题，该提案的目的是1） 急性后共证于199次后遗症（PACS）诱导器官纤维化和TO的翻译模型 使用此模型2）严格评估潜在的预防性，抗纤维化的效率 由肺部治疗公司（LTI）获得了治疗性Petides专利和开发的。减少 在人类纤维化组织中观察到小窝蛋白-1的表达，组织病理学表明， 内源性CAV-1蛋白表达显着降低了10个独特的致命共证 肺。此外，在PACS组织样品中降低了Cav-1 RNA 该模型将得出。 LTI的Caveolin-1专利投资组合的抗纤维化活性 通过7个氨基酸序列赋予脚手架结构域（CSD）肽 fttftvt。 7-Mer被配制为遗传干粉，目前正在进行 1阶段的安全性，耐受性和药代动力学研究（NCT04233814） 在多个体内临床前模型的真皮临床前模型中逆转纤维化的能力， 心脏和肺纤维化（PF），并减弱多个促纤维化信号通路 体外。但是，鉴于在此试验中观察到20mg的剂量限制，PACS具有 观察到除了肺和系统性脉管系统外，还会影响其他器官 更固体，稳定，XR，皮下，可注射版的LTI-03，称为LTI-2355。 lti- 2355在各种人类 和啮齿动物纤维化模型。此外，我们的仓库上的初步PK数据扩展版本 （xr）公式表明它是稳定的，在一次注射后在肺中可用 在推定的理论剂量水平为14至22天。鉴于我们在IPF- SCID小鼠系统，我们假设稳健的肺纤维化，并可能发展 在静脉注射人类肺后，多器官纤维化将发展 从丢弃的肺肺移植（病毒滴度阴性）中的细胞中。如果 成功建立，我们不仅将测试三个推定的扩展释放（XR） 在这种新颖的PACS模型中的治疗性琐碎，但我们还将发布这些方法和 模型的特征，该模型可能成为测试的重要工具 推定的PACS介入疗法。综上所述，我们建议建立一个 PAC的翻译小鼠模型，并通过测试三项专利的LTI-2355-XR公式 （SC）交付和比较不适合对照肽和Nintedanib（标准） IPF的护理和PAC治疗的当前候选人（Pincer，NCT04856111）。待办的 有效的结果（促炎和促纤维化指标的综合降低AT 至少40％，将选择牵头候选人，并将提交II期SBIR以支持 进一步的临床开发（PK/PD，特定于SC公式的毒理学，IND支持 工作）。该建议符合包括肽在内的团队的总优势 形成，在翻译的小鼠模型的生化评估中的专业知识 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，该项目具有产生新疗法的强大潜力 Pacs。