LUNG THERAPEUTICS INC — Department of Health and Human Services SBIR Phase I: NHLBI

Description

Abstract The pathogenesis of interstitial lung diseasesincluding idiopathic pulmonary fibrosisIPFis characterized by alveolar epithelial cellAECapoptosisproliferation and accumulation of activated myofibroblasts and fibrotic lung fibroblastsFLFsextracellular matrixECMdeposition and fibrosisresulting in progressive dyspnea and loss of lung functionCharacteristic morphological lesions include spatial and temporal heterogeneity incorporating areas of normal lung adjacent to areas of evolving fibrosis containing FLFsWe found that increased pcontributes to AEC apoptosisfibroblast activation and subsequent development of PFIPF is a progressive and fatal lung diseasecases perindividuals in the US annuallywith a median five year survival of onlyThere is presently no cureRecentlypharmacotherapy has been shown to slow progression of diseasesuggesting the possibility that even better treatment can be developedWe identified a caveolinscaffolding domainmer peptideFTTFTVTLTIpreviously called CSPthat inhibits pAEC apoptosis and the development of PF in mice after bleomycinBLMinduced lung injuryWe also discovered that basal expression of pis markedly reduced in proliferating FLFs isolated from the lungs of patients with IPF and mice with established PF induced by BLMLTIinhibits degradation of pdue to increased mdmexpression in FLFsrestores levels of pand blocks proliferation of FLFsLTIis well toleratedcan be delivered via the airwayattenuates PF in mice with either established BLMor TGF b induced PF when injected intraperitoneallymg kgWe have developed a dry powder formulation of LTIwith ideal particle characteristics for inhalationis excipient freecost effectiveand toxicology in rats and dogs suggest it is safe and well toleratedThis powder formulation has ideal particle properties for direct pulmonary delivery using a dry powder inhaler clinicallyIn this proposal we aim to develop a scrambled peptide control dry powder to be administered daily fordays startingdays after initial injury as a control for LTIefficacy testing in two PF modelsAimEfficacy will be measured using lung functionimaging and standard histological and biochemical endpoints in the bleomycin model as well as the TGFb modelThe 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 LTIThe proposal caters to the aggregate strengths of the team in drug discoveryformulationthe use of animal models of lung diseases and airway deliveryLastlythis project has a strong potential of yielding a newsafeconvenient 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 Narrative There is no cure for idiopathic pulmonary fibrosisIPFa progressive fatal disease that affects thousands of US patients annuallyIt has been demonstrated that a critical protein known as caveolinis present at reduced levels in diseased lung tissues from IPF patients relative to the lung tissues from normal humans without IPFThis 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