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.

摘要 SARS-CoV-2感染引起的急性呼吸窘迫综合征（ARDS）激活了许多肺 在特发性肺纤维化（IPF）中观察到重塑途径，报告表明 约33%的住院患者的症状持续2至12个月或更长时间 患者为了解决这一新出现的健康问题，本提案旨在1）制定一个 急性COVID-19后遗症（PACS）诱导的器官纤维化的转化模型， 使用该模型2）严格评估潜在的预防性、抗纤维化 由Lung Therapeutics，Inc（LTI）获得专利并开发的治疗肽。减少 在人类纤维化组织中观察到小窝蛋白-1表达，组织病理学显示， 内源性CAV-1蛋白表达在10种独特的致死性COVID中显著降低 肺此外，CAV-1 RNA在PAC组织样品中减少， 这个模型将被导出。LTI的专利产品Caveolin-1的抗纤维化活性 支架结构域（CSD）肽通过7个氨基酸序列赋予 FTTFTVT。 7-mer被配制成吸入干粉，目前正在进行一项研究。 I期安全性、耐受性和药代动力学研究（NCT 04233814），正如其所证明的 在多种真皮的体内临床前模型中逆转已建立的纤维化的能力， 心脏和肺纤维化（PF），并减弱多种促纤维化信号通路 体外然而，鉴于在本试验中观察到的剂量限制为20 mg，并且PACS已 已观察到影响除肺以外的其他器官以及全身血管系统， LTI-03的更可溶、更稳定、XR、皮下注射版本，称为LTI-2355。LTI- 2355已在多种人类中显示出强有力的抗炎和抗纤维化作用。 和啮齿动物纤维化模型。此外，我们的长效制剂（缓释）的初步PK数据 (XR)制剂表明其在单次注射后在肺中是稳定和可用的 在假定的治疗剂量水平下，持续14至22天。根据我们在森林小组的经验- 在SCID小鼠系统中，我们假设可能发展为肺纤维化的稳健肺纤维化， 多器官纤维化将在静脉内施用活的人肺 从废弃的COVID肺移植物（病毒滴度阴性）中提取的细胞移植到SCID小鼠中。如果 成功建立，我们不仅将测试三个假定的延长释放（XR） 在这个新的PACS模型中，我们还将公布这些方法和 模型的特性，这可能成为一个重要的测试工具， 假定的PACS介入治疗。综合而言，我们建议设立一个 翻译小鼠模型的PACS，并测试三个专利的LTI-2355-XR配方，通过 (SC)递送并与对照肽和NCL 4（标准）的功效进行比较。 治疗IPF，目前是PACS治疗的候选药物（PINCER，NCT 04856111）。未决 有效的结果（AT的促炎性和促纤维化指标的复合降低 至少40%，将选择一名主要候选人，并提交第二阶段SBIR，以支持 进一步临床开发（PK/PD、SC制剂特异性毒理学、IND支持性 工作）。这个建议迎合了团队的总实力，包括肽 制剂，在翻译小鼠模型的生化评估的专业知识， 肺纤维化、免疫学、器官纤维化、药代动力学和总体药物 发展最后，该项目具有很强的潜力，以产生一种新的治疗方法， 的PACS。