Preclinical development of inhalable glutaredoxin-1 for the treatment of IPF

DESCRIPTIONprovided by applicantIdiopathic pulmonary fibrosisIPFkills aboutpersons in the United States each yearThere are currently aroundAmericans afflicted with this fatal disease that typically results in death withinyearsThis year alone another approximatelyAmericans will receive this devastating diagnosisWhile two recently approved drugs reduce the time to decline in certain lung parametersand the risk for acute exacerbationsthere is no currently available approachbeyond lung transplantationthat has been proven to extend the lives of IPF patientsOur ultimate goal is to improve the lives of patients faced with this grim prognosis by developing a safe and effectiveinhalable therapeutic to haltand possibly reversethe fibrotic process underlying IPF pathogenesisWe have identified the redox regulating enzymeglutaredoxinGrxas a promising therapeutic candidateOur studies using the well established bleomycin and TGFlung fibrosis models in mice have demonstrated thatGrxknockout mice develop markedly more severe lung damage than control micemice that overexpress Grxin epithelial cells are protected from fibrosisandaerosol delivery of recombinant Grxreverses multiple parameters of lung pathology even in aged miceand even when administered after establishment of fibrotic alterationsAs Grxis highly conserved in all mammalswe anticipate that human recombinant Grxwill have similar effectsOur development plan includes a collaboration with PulmatrixInca company with a proven track record for incorporating large molecules into their proprietary iSPERSE dry powder formulationand advancing clinical development of such for serious respiratory conditions like cystic fibrosisIn Phase I of this application we propose to produce a murine recombinant GrxiSPERSE proprietary dry powder formulationiSPERSEPulmatrixIncand optimize both process conditions and excipientsWe will then perform in vitro and in vivo testing to confirm equivalence and determine the maximum tolerated doseMTDin miceIn Phase IIwe will complete murine efficacy studies and then identifydevelop and characterize a lead formulation for the clinical grade producta human GrxiSPERSE dry powder formulationand conduct nonclinical safety and toxicity studies with this product in rats and monkeysUpon successful completion of non clinical safety and toxicity studieswe will submit an IND to pursue clinical studies with our novel inhalable productThe successful development of inhalable human GrxiSPERSE would result in an entirely new approach to treat IPFThis application describes the work necessary to complete preclinical developmentand will position GrxiSPERSE for initial clinical trials