The pathogenesis of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), is characterized by alveolar epithelial cell (AEC) apoptosis, proliferation and accumulation of activated myofibroblasts and fibrotic lung fibroblasts (FLFs), extracellular matrix (ECM) deposition and fibrosis, resulting in progressive dyspnea and loss of lung function. Characteristic morphological lesions include spatial and temporal heterogeneity incorporating areas of normal lung adjacent to areas of evolving fibrosis-containing FLFs. We found that increased p53 contributes to AEC apoptosis, fibroblast activation and subsequent development of PF. IPF is a progressive and fatal lung disease (6.8-16.3 cases per 100,000 individuals in the US annually) with a median five-year survival of only 20%. There is presently no cure. Recently, pharmacotherapy has been shown to slow progression of disease, suggesting the possibility that even better treatment can be developed. We identified a caveolin-1 scaffolding domain 7-mer peptide (FTTFTVT), LTI-03 (previously called CSP7), that inhibits p53, AEC apoptosis and the development of PF in mice after bleomycin (BLM)-induced lung injury. We also discovered that basal expression of p53 is markedly reduced in proliferating FLFs isolated from the lungs of patients with IPF and mice with established PF induced by BLM. LTI-03 inhibits degradation of p53 due to increased mdm2 expression in FLFs, restores levels of p53 and blocks proliferation of FLFs. LTI-03 is well-tolerated, can be delivered via the airway, attenuates PF in mice with either established BLM- or TGF-b-induced PF when injected intraperitoneally (1.5mg/kg). We have developed a dry powder formulation of LTI-03 with ideal particle characteristics for inhalation, is excipient free, cost effective, and toxicology in rats and dogs suggest it is safe and well tolerated. This powder formulation has ideal particle properties for direct pulmonary delivery using a dry powder inhaler clinically. In this proposal we aim to develop a scrambled peptide control dry powder to be administered daily for 7 days starting 14 days after initial injury as a control for LTI-03 efficacy testing in two PF models (Aim2). Efficacy will be measured using lung function, imaging and standard histological and biochemical endpoints in the bleomycin model as well as the TGFb model. The objective of this study is to develop preclinical pharmacology data such that a Phase II proposal can be submitted to provide funds for a first in human study of this DPI formulation of LTI-03. The proposal caters to the aggregate strengths of the team in drug discovery, formulation, the use of animal models of lung diseases and airway delivery. Lastly, this project has a strong potential of yielding a new, safe, convenient and more effective intervention for patients with IPF or other interstitial lung diseases for whom cure is unavailable and alternative drug options that can reliably improve outcomes remain limited.
Public Health Relevance Statement: Narrative There is no cure for idiopathic pulmonary fibrosis (IPF), a progressive fatal disease that affects thousands of US patients annually. It has been demonstrated that a critical protein known as caveolin-1 is present at reduced levels in diseased lung tissues from IPF patients relative to the lung tissues from normal humans without IPF. This project will advance development of a novel therapeutic candidate to treat IPF in man by establishing a dry powder inhaler formulation and testing the dry powder formulations in mouse models of IPF.
Project Terms: Acute; Advanced Development; Affect; Alveolar; Animal Model; Animals; Apoptosis; Area; Asthma; Attenuated; base; Biochemical; Bleomycin; C57BL/6 Mouse; Caliber; Canis familiaris; caveolin 1; Cells; Characteristics; Chronic Obstructive Airway Disease; Clinical; Clinical Trials; Collagen; cost effective; Data; Deposition; design; Development; Diagnosis; Disease; Disease Progression; drug discovery; Dyspnea; effective intervention; efficacy study; efficacy testing; Epithelial Cells; Excipients; Extracellular Matrix; Extracellular Matrix Proteins; Felis catus; Female; Fibroblasts; Fibrosis; fine particles; first-in-human; Formulation; Functional disorder; Funding; Grant; Heterogeneity; Histologic; Histology; Human; human study; idiopathic pulmonary fibrosis; Image; improved; improved outcome; In Vitro; in vivo; Incidence; indium-bleomycin; Individual; Inhalation; Inhalators; Injury; Interstitial Lung Diseases; Intervention; intraperitoneal; Lead; Lesion by Morphology; Literature; Lung; Lung diseases; lung injury; man; Measures; Mediating; Methods; Modeling; mouse model; Mus; Myofibroblast; Normal tissue morphology; novel therapeutics; Oral Administration; Orphan; particle; Pathogenesis; Patients; Peptides; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Pharmacy (field); Phase; Pilot Projects; Pirfenidone; Powder dose form; pre-clinical; Pre-Clinical Model; preclinical development; preclinical study; Preclinical Testing; Proliferating; Property; Proteins; Publishing; Pulmonary Fibrosis; pulmonary function; Rattus; recruit; Replacement Therapy; Reporting; Respiratory physiology; Rodent; Rodent Model; scaffold; Seminal; Signal Pathway; Slice; Small Business Innovation Research Grant; stability testing; Structure of parenchyma of lung; System; Technology; Testing; Therapeutic; therapeutic candidate; Therapeutic Intervention; Tissues; Toxicology; TP53 gene; Transforming Growth Factor beta; Treatment Efficacy; treatment strategy; Tyrosine Kinase Inhibitor
