Friday, November 22, 2024
11/22/2024
Interstitial lung diseases (ILDs) are characterized by progressive pulmonary scarring. Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of ILDs and is a fatal lung disease with an incidence of 60 cases/100,000 individuals in the US annually. IPF has a median five-year survival of only 20%. There is presently no cure. The pathogenesis of IPF is characterized by alveolar epithelial cell (AEC) senescence and apoptosis, proliferation and accumulation of activated myofibroblasts and fibrotic lung fibroblasts (fLfs) and extracellular matrix deposition. These features lead to progressive lung dysfunction. Morphologic changes include spatial and temporal heterogeneity incorporating areas of normal lung adjacent to diseased areas containing apoptotic AECs, and fLfs. Recently, pharmacotherapy has been shown to slow progression of IPF, suggest that even more effective treatment can be developed. We found that increased p53 contributes to AEC apoptosis and fibroblast activation, and that its decline in fLfs promotes myofibroblast expansion. We also found that caveolin-1 (Cav1) is increased in injured AECs while its level is markedly reduced in proliferating fLfs from the lungs of IPF patients and mice with established PF. We identified a 20-mer Cav1 scaffolding domain peptide (CSP), and its truncated 7-mer fragment, CSP7, that inhibits p53, TGF-β, CTGF, AEC apoptosis and fLf expansion. These peptides block PF in mice after single (1X) or multi-hit (8X) bleomycin (BLM), adenoviral TGF-β1 (Ad-TGF-β1)- and silica- induced lung injury. CSP7 inhibits degradation of p53 due to increased mdm2 expression in fLfs and blocks their proliferation. CSP7 also inhibits AEC senescence and apoptosis, which are otherwise increased in fibrotic lungs, including in IPF. CSP7 is well-tolerated in mice and can effectively be delivered via the airways. Our work validates Cav1 as a therapeutic target in PF. Our publications offer the premise for developing CSP7 for airway delivery by nebulization (neb) or dry power inhalation (DPI) as a new, safe and more effective therapy for PF. In Aim I, we will define cell surface binding/mode action of CSP7, optimize the structure of CSP7, identify the range of dosing for effective airway (neb or DPI) delivery and assess the tolerability and ability of CSP7 to resolve PF in 4 (1X BLM in young and aged mice, Ad-TGF-β1 and 8X BLM) models of PF. In Aim II, we will select the most effective, well-tolerated, optimized form CSP7s (CSP7OPs) identified in Aim I, then evaluate non-GLP pharmacokinetics, toxicology and evaluate systemic biodistribution after airway delivery. In Aim III, we will elucidate the molecular mechanisms by which CSP7OP combined with pirfenidone or nintedanib, affects injured AECs and fLfs to resolve existing PF. Targeting Cav1 with CSP7 represents a novel and promising approach for treatment of IPF via the airway. This project has a high probability of success and the data to be generated is a predicate for IND-enabling work. Our team has all the requisite expertise in cellular/molecular biology, preclinical modeling, drug discovery, formulation and airway drug delivery. This project will likely define novel and potentially more effective therapy for patients with IPF or other ILDs, for whom effective treatment options remain limited.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
