Project Grant R41HL174346

REPURPOSING OF FDA-APPROVED NRF2 ACTIVATORS AS A NOVEL INHALED THERAPY FOR PULMONARY FIBROSIS - ABSTRACT: FIBROTIC DISORDERS REPRESENT A MAJOR HEALTH PROBLEM IN THE U.S., WITH A RISING INCIDENCE (PARTICULARLY AMONG THE ELDERLY). IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A RELENTLESS AND FATAL FIBROTIC DISEASE, CHARACTERIZED BY PROGRESSIVE SCAR TISSUE FORMATION IN THE LUNGS, RESULTING IN RESPIRATORY FAILURE. THERE ARE TWO FDA-APPROVED ORAL DRUGS FOR IPF, WHICH OFFER ONLY MODEST IMPROVEMENTS IN SLOWING THE LUNG FUNCTION DECLINE AND PATIENT SURVIVAL. ONE POSSIBLE EXPLANATION FOR THE LIMITED THERAPIES AVAILABLE IS THAT AGE-DEPENDENT PATHOLOGIC MECHANISMS REMAIN LARGELY UNEXPLOITED IN THE DRUG DEVELOPMENT PROCESS, DESPITE THE FACT THAT AGING HAS BEEN STRONGLY IMPLICATED IN THE PATHOGENESIS OF IPF. WE WERE THE FIRST TO DEMONSTRATE THAT THE KEY EFFECTOR CELLS IN FIBROGENESIS, MYOFIBROBLASTS, EXHIBIT REDOX IMBALANCE IN AGING; THIS IS IN PART REGULATED BY A DEFICIENT INDUCTION OF A MASTER REGULATOR OF ANTIOXIDANT RESPONSES, NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2). HUMAN PATIENTS WITH IPF EXHIBIT DECREASED NRF2 EXPRESSION IN MYOFIBROBLASTIC FOCI, SUPPORTING THIS CELLULAR REDOX IMBALANCE IN FIBROTIC DISEASE. WE HAVE ALSO DEMONSTRATED THAT IN CONTRAST TO SELF-LIMITED, RESOLVING FIBROSIS IN YOUNG MICE, AGED MICE EXHIBIT DEFECTIVE NRF2-MEDIATED ANTIOXIDANT RESPONSES, WHICH PROMOTE AGE-DEPENDENT PERSISTENT LUNG FIBROSIS. THESE FINDINGS MAY HELP TO EXPLAIN WHY FIBROTIC DISORDERS ARE MORE PREVALENT AMONG THE ELDERLY. ALTHOUGH THERAPEUTIC STRATEGIES TARGETING NRF2 TO TREAT IPF HOLD PROMISE, THE SYSTEMIC DELIVERY OF NRF2 ACTIVATORS HAS BEEN STYMIED BY SAFETY CONCERNS. A BREAKTHROUGH IN THIS FIELD MAY LIE IN THE REPURPOSING OF DIMETHYL FUMARATE (DMF), AN FDA- APPROVED ORAL DRUG FOR MULTIPLE SCLEROSIS KNOWN TO ACTIVATE NRF2. RECENTLY, WE HAVE DEMONSTRATED THAT INHALED DMF TREATMENT RESTORES NRF2-MEDIATED ANTIOXIDANT RESPONSES AND PROMOTES REVERSAL OF ESTABLISHED LUNG FIBROSIS AT JUST A FRACTION OF THE ORAL DOSE IN AN AGING MURINE MODEL. ALTHOUGH WE HAVE DEMONSTRATED IMPORTANT PROOF-OF- CONCEPT FOR THE REPURPOSING OF DMF AS INHALED THERAPY FOR IPF, THE CLINICAL TRANSLATABILITY OF INHALED NRF2 THERAPY FOR IPF REMAINS UNKNOWN. THIS PHASE 1 STTR APPLICATION PIVOTS TO THE EXPLORATION OF THREE FDA-APPROVED NRF2 ACTIVATORS (DMF, DIROXIMEL FUMARATE, AND MONOMETHYL FUMARATE) AS REPURPOSED INHALED THERAPY FOR IPF. THE GOAL OF THE PROPOSED STUDY IS TO ASSESS THE CLINICAL TRANSLATABILITY OF INHALED NRF2 THERAPY FOR IPF BY EVALUATING THE PHARMACOLOGY AND TOXICOLOGY OF LUNG-TARGETED NRF2 ACTIVATOR THERAPY IN RODENT MODELS. AIM 1 WILL EVALUATE THE EFFICACY OF THREE FDA-APPROVED NRF2 ACTIVATORS IN HUMAN EX VIVO MODEL USING BIOACTIVE PRECISION CUT LUNG SLICES AND NOMINATE THE TOP CANDIDATE. AIM 2 WILL CHARACTERIZE THE PHARMACOKINETIC PROFILES. AIM 3 WILL DETERMINE THE THERAPEUTIC INDEX AND MAXIMUM TOLERATED DOSE OF THE TOP CANDIDATE (IDENTIFIED FROM AIMS 1-2). TO DATE, NO THERAPEUTICS HAVE BEEN SHOWN TO REVERSE AGE-ASSOCIATED ESTABLISHED FIBROSIS, WHICH MAY REPRESENT THE HOLY GRAIL FOR THERAPEUTIC STRATEGIES TO MORE EFFECTIVELY TREAT IPF. WE HYPOTHESIZE THAT THERAPEUTIC STRATEGIES TARGETING AGE-ASSOCIATED PATHOLOGIC MECHANISMS (E.G. AGE-DEPENDENT DEFECTIVE NRF2-MEDIATED ANTIOXIDANT RESPONSES) OFFER THE GREATEST POTENTIAL FOR DEVELOPING SUCCESSFUL IPF TREATMENTS.