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

点击翻译按钮获取中文摘要

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.