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.
Public Health Relevance Statement: Narrative Acute SARS-CoV-2 infection invokes maladapted tissue remodeling leading to persistent pulmonary symptoms and re-hospitalization. To address this emerging public health concern, this proposal aims to 1) develop a translational model of post-acute sequalae of COVID-19 (PACS) induced organ fibrosis and to utilize this model to 2) rigorously assess efficacy of an anti-inflammatory and antifibrotic therapeutic patented and developed by Lung Therapeutics, Inc (LTI). Taken together, this project aims to develop a therapeutic intervention for hospitalized SARS-CoV-2 patients who are at high risk for developing PACS.
Project Terms: Primary Protein Structure; protein sequence; Amino Acid Sequence; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Anti-Inflammatory Agents; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Bleomycin; Bleo; Blood; Blood Reticuloendothelial System; Cells; Cell Body; Clinical Trials; intravenous administration; Fibrosis; Foundations; Goals; Health; Heart; Hospitalization; Hospital Admission; Human; Modern Man; Hydroxyproline; 4 Hydroxyproline; Oxyproline; In Vitro; Infection; Inflammation; Kidney; Kidney Urinary System; renal; Lead; Pb element; heavy metal Pb; heavy metal lead; Lung; Lung Respiratory System; pulmonary; Lung Transplantation; Lung Grafting; Pulmonary Graft; Pulmonary Transplant; Pulmonary Transplantation; lung transplant; Methods; Genetic Models; Mus; Mice; Mice Mammals; Murine; Legal patent; Patents; Patients; Peptides; Drug Kinetics; Pharmacokinetics; Pilot Projects; pilot study; Powder dose form; Powders; Public Health; Publishing; Pulmonary Fibrosis; Lung Tissue Fibrosis; fibrosis in the lung; lung fibrosis; Acute Respiratory Distress Syndrome; ARDS; Acute Respiratory Distress; Adult ARDS; Adult RDS; Adult Respiratory Distress Syndrome; Da Nang Lung; Shock Lung; Stiff lung; wet lung; RNA; Non-Polyadenylated RNA; RNA Gene Products; Ribonucleic Acid; Rodent; Rodentia; Rodents Mammals; Safety; Signal Pathway; Testing; Time; Tissues; Body Tissues; Toxicology; Work; Trichrome stain; cytokine; Severe Combined Immunodeficient Mice; SCID Mice; Injectable; Immunology; Peptide Domain; Protein Domains; Tertiary Protein Structure; injuries; Injury; Organ; Acute; Phase; Biochemical; Therapeutic; Attenuated; attenuate; attenuates; Inflammatory; tool; scaffold; scaffolding; caveolin 1; 22kD Caveolae Protein; Caveolin 1, Caveolae Protein, 22kD; VIP21; VIP21 protein; vesicular integral membrane protein 21 kDa; subcutaneous; subdermal; Slide; prophylactic; cell type; System; Viral; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Organ Harvestings; coronary fibrosis; cardiac fibrosis; myocardial fibrosis; experience; interstitial; cohort; Animal Model; Animal Models and Related Studies; model of animal; attenuation; hospital readmission; hospital re-admission; re-admission; re-hospitalization; readmission; rehospitalization; synthetic polymer Bioplex; bioplex; Histopathology; novel; Reporting; Therapeutic Intervention; intervention therapy; Modeling; drug development; protein expression; Non-specific Interstitial Pneumonia; Nonspecific Interstitial Pneumonia; Tissue Sample; Address; Dose; Symptoms; Data; Dose Limiting; Dryness; Harvest; Molecular Analysis; Pre-Clinical Model; Preclinical Models; Research Contracts; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Characteristics; Development; developmental; Pathway interactions; pathway; injured; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; Outcome; Cellular model; Cell model; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; high risk; standard of care; cutaneous fibrosis; dermal fibrosis; fibrotic skin; skin fibrosis; Formulation; Peptide-based drug; therapeutic peptide; peptide drug; clinical development; Injections; Inhaling; Inhalation; lead candidate; translational model; Fibrosing Alveolitis; diffuse interstitial pulmonary fibrosis; idiopathic pulmonary fibrosis; COVID19; CV-19; CV19; corona virus disease 2019; coronavirus disease 2019; coronavirus disease-19; coronavirus infectious disease-19; COVID-19; CoV disease; corona virus disease; COVID; coronavirus disease; COVID associated ARDS; COVID associated acute respiratory distress syndrome; COVID induced ARDS; COVID induced acute respiratory distress syndrome; COVID related ARDS; COVID related acute respiratory distress syndrome; COVID-19 associated ARDS; COVID-19 associated acute respiratory distress syndrome; COVID-19 induced ARDS; COVID-19 induced acute respiratory distress syndrome; COVID-19 related ARDS; COVID-19 related acute respiratory distress syndrome; COVID-19/acute respiratory distress syndrome; COVID/ARDS; COVID/acute respiratory distress syndrome; COVID19 associated ARDS; COVID19 associated acute respiratory distress syndrome; COVID19 induced ARDS; COVID19 induced acute respiratory distress syndrome; COVID19 related ARDS; COVID19 related acute respiratory distress syndrome; COVID19/ARDS; COVID19/acute respiratory distress syndrome; SARS-CoV-2 associated ARDS; SARS-CoV-2 associated acute respiratory distress syndrome; SARS-CoV-2 induced ARDS; SARS-CoV-2 induced acute respiratory distress syndrome; SARS-CoV-2 related ARDS; SARS-CoV-2 related acute respiratory distress syndrome; SARS-CoV-2/ARDS; SARS-CoV-2/acute respiratory distress syndrome; coronavirus disease 2019 associated ARDS; coronavirus disease 2019 associated acute respiratory distress syndrome; coronavirus disease 2019 induced ARDS; coronavirus disease 2019 induced acute respiratory distress syndrome; coronavirus disease 2019 related ARDS; coronavirus disease 2019 related acute respiratory distress syndrome; coronavirus disease 2019/ARDS; coronavirus disease 2019/acute respiratory distress syndrome; coronavirus disease associated ARDS; coronavirus disease associated acute respiratory distress syndrome; coronavirus disease induced ARDS; coronavirus disease induced acute respiratory distress syndrome; coronavirus disease related ARDS; coronavirus disease related acute respiratory distress syndrome; coronavirus disease/ARDS; coronavirus disease/acute respiratory distress syndrome; severe acute respiratory syndrome coronavirus 2 associated ARDS; severe acute respiratory syndrome coronavirus 2 associated acute respiratory distress syndrome; severe acute respiratory syndrome coronavirus 2 induced ARDS; severe acute respiratory syndrome coronavirus 2 induced acute respiratory distress syndrome; severe acute respiratory syndrome coronavirus 2 related ARDS; severe acute respiratory syndrome coronavirus 2 related acute respiratory distress syndrome; severe acute respiratory syndrome coronavirus 2/ARDS; severe acute respiratory syndrome coronavirus 2/acute respiratory distress syndrome; COVID-19/ARDS; COVID infected patient; COVID patient; COVID positive patient; COVID-19 infected patient; COVID-19 positive patient; COVID19 patient; COVID19 positive patient; SARS-CoV-2 infected patient; SARS-CoV-2 patient; SARS-CoV-2 positive patient; coronavirus disease 2019 infected patient; coronavirus disease 2019 patient; coronavirus disease 2019 positive patient; coronavirus disease infected patient; coronavirus disease patient; coronavirus disease positive patient; coronavirus disease-19 patient; coronavirus patient; patient infected with COVID; patient infected with COVID-19; patient infected with SARS-CoV-2; patient infected with coronavirus disease; patient infected with coronavirus disease 2019; patient infected with severe acute respiratory syndrome coronavirus 2; patient with COVID; patient with COVID-19; patient with COVID19; patient with SARS-CoV-2; patient with coronavirus disease; patient with coronavirus disease 2019; patient with severe acute respiratory distress syndrome coronavirus 2; severe acute respiratory syndrome coronavirus 2 infected patient; severe acute respiratory syndrome coronavirus 2 patient; severe acute respiratory syndrome coronavirus 2 positive patient; COVID-19 patient; COVID-19 infection; COVID-19 virus infection; COVID19 infection; SARS-CoV2 infection; Severe acute respiratory syndrome coronavirus 2 infection; coronavirus disease 2019 infection; infected with COVID-19; infected with COVID19; infected with SARS-CoV-2; infected with SARS-CoV2; infected with coronavirus disease 2019; infected with severe acute respiratory syndrome coronavirus 2; SARS-CoV-2 infection; Profibrotic signal; Profibrotic factor; nintedanib; Ofev; Post-Acute Sequelae of SARS-CoV-2 Infection; PASC; Post Acute Sequelae of COVID19; Post Acute Sequelae of SARS-CoV-2; Post Acute Sequelae of SARS-CoV2; Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2; adverse sequelae of COVID; adverse sequelae of COVID-19; adverse sequelae of coronavirus disease; adverse sequelae of coronavirus disease 2019; chronic COVID-19 sequelae; long haul sequelae of COVID-19; long haul sequelae of coronavirus disease 2019; long-term sequelae of COVID-19; long-term sequelae of SARS-CoV-2; long-term sequelae of coronavirus disease 2019; long-term sequelae of severe acute respiratory syndrome coronavirus 2; post-acute sequelae following SARS-CoV-2 infection; post-acute sequelae of COVID-19; post-acute sequelae of acute COVID infection; post-acute sequelae of coronavirus disease 2019; pulmonary symptom; Lung symptom; comparison control; compare to control
