Project Grant R43HL162135

DEVELOPING NON-ANTICOAGULANT RECOMBINANT HEPARIN FOR TREATING THE COPD PATHOGENIC TRIAD - PROJECT SUMMARY THIS PROPOSAL DESCRIBES A NOVEL STRATEGY TO TREAT EMPHYSEMA IN COPD (CHRONIC OBSTRUCTIVE PULMONARY DISEASE) USING UNIQUELY TAILORED HEPARAN SULFATE PRODUCED FROM GENETICALLY ENGINEERED MAMMALIAN CELLS. EMPHYSEMA IS A MAJOR COMPONENT OF COPD, A DISEASE THAT AFFLICTS UP TO 5% OF THE POPULATION AND IS THE 4TH LEADING CAUSE OF DEATH IN THE US. THERE IS CURRENTLY NO DRUG THAT HAS PROVEN EFFICACIOUS TO CURE OR DELAY PROGRESSION OF THE DISEASE. WHILE TARGETED THERAPIES HAVE SHOWN LITTLE CLINICAL BENEFIT, HEPARIN HAS MULTI-POINT INHIBITORY ACTIVITY AGAINST THE THREE MAJOR DRIVERS OF DISEASE PROGRESSION (PROTEASES, OXIDATIVE STRESS AND INFLAMMATION) AND CAN BE INHALED FOR LOCAL TREATMENT. HEPARIN'S USEFULNESS IS LIMITED BY ITS ANTICOAGULANT ACTIVITY. TEGA THERAPEUTICS' RECOMBINANT HEPARAN SULFATE PRODUCTION TECHNOLOGY ENABLES TARGETED ELIMINATION OF 3-O-SULFATE GROUPS THAT ARE ESSENTIAL FOR ANTICOAGULANT ACTIVITY WHILE MAINTAINING ANTI-ELASTOLYTIC, ANTI- OXIDATIVE AND ANTI-INFLAMMATORY PROPERTIES. MAMMALIAN CELL LINES THAT PRODUCE HEPARAN SULFATE WITHOUT 3-O- SULFATE WILL BE GENETICALLY ENGINEERED TO IMPROVE INHIBITION OF EMPHYSEMA DRIVERS. THE PRODUCTS WILL THEN BE TESTED TO EVALUATE THEIR ABILITY TO INHIBIT PROTEASES, OXIDATIVE STRESS AND INFLAMMATORY MEDIATORS IN VITRO. FINALLY, THE EFFICACY OF THE TOP CANDIDATE WILL BE ASSESSED THROUGH OROTRACHEAL DELIVERY IN A RAT MODEL OF EMPHYSEMA. THE RESULTING PRODUCT WILL BE FURTHER DEVELOPED AS AN INHALABLE DRUG IN PHASE II THROUGH BIOPROCESS DEVELOPMENT, FORMULATION, TOXICOLOGY STUDIES AND PHARMACOKINETIC STUDIES. SUCCESS IN THIS ENDEAVOR WILL YIELD A CLINICAL DRUG THAT LIMITS THE PROGRESSION OF EMPHYSEMA AND INCREASES THE DURATION AND QUALITY OF LIFE FOR PATIENTS. IT WOULD LIKELY ALSO BE USEFUL FOR OTHER CHRONIC PULMONARY DISEASES INCLUDING CYSTIC FIBROSIS AND ALPHA- 1 ANTITRYPSIN DEFICIENCY.