Project Grant R44EY035188

A SINGLE DOSE ANTI-SCARRING THERAPEUTIC FOR THE CORNEA - ABSTRACT DUB BIOLOGICS IS DEVELOPING A THERAPEUTIC FOR THE PREVENTION AND TREATMENT OF CORNEAL SCARRING THROUGH KNOCKDOWN OF A NOVEL TARGET THAT HAS BEEN SHOWN TO BE CENTRAL TO THE FIBROTIC RESPONSE LEADING TO CORNEAL OPACIFICATION. CORNEAL OPACIFICATION SEVERELY IMPAIRS THE VISION OF 4.2 MILLION PEOPLE AROUND THE WORLD, 5.1% OF THE TOTAL BLIND POPULATION. MONOCULAR SCARRING IS FAR MORE COMMON, AFFECTING 3X AS MANY PEOPLE. SCARRING IN THE CORNEA RESULTING FROM INJURY, TRAUMA, OR INFECTION CAN LEAD TO DEBILITATING OPACITIES AND PERMANENT VISION LOSS. TREATMENTS TO PREVENT SCARRING INCLUDE CORTICOSTEROIDS HOWEVER, THEY HAVE UNPREDICTABLE RESULTS AND CAUSE WELL- ESTABLISHED ADVERSE EVENTS THAT INCLUDE CATARACTS AND GLAUCOMA. ONCE OPACIFICATION OCCURS, IT IS MOST OFTEN IRREVERSIBLE AND THE ONLY OPTION FOR PATIENTS ARE CORNEAL TRANSPLANTS. HOWEVER, ONLY 1 IN EVERY 80 CORNEAS NEEDED FOR TRANSPLANT ARE AVAILABLE. THEREFORE, PREVENTING OPACIFICATION IS OF UTMOST IMPORTANCE. DUB BIOLOGICS HAS IDENTIFIED A NOVEL SCARRING PATHWAY IN THE CORNEA, CENTRAL TO WHICH IS THE DEUBIQUITINASE USP10. USP10 ACTIVITY IN THE CORNEA FOLLOWING INJURY CAN BE MODULATED THROUGH KNOCKDOWN OF USP10 WITH A SELF-DELIVERY SIRNA (SDRNA). DUB BIOLOGICS' DRUG IS A FULLY MODIFIED SDRNA CONJUGATED TO A CHOLESTEROL MOIETY THAT DOES NOT NEED ENCAPSULATION FOR DELIVERY. USP10-TARGETING SDRNA (SDUSP10) IS EFFECTIVELY DELIVERED TO THE CORNEA VIA EYE DROPS. ADDITIONALLY, SDUSP10 IS RESISTANT TO NUCLEASES, IS NOT IMMUNOGENIC, AND DEMONSTRATES IN VIVO EFFICACY FOR MONTHS AFTER A SINGLE TREATMENT. PREVIOUS WORK HAS FOCUSED ON MECHANISTIC STUDIES USING HUMAN PRIMARY CORNEAL STROMAL FIBROBLASTS, CORNEAL STROMAL WOUND HEALING MODELS IN MICE AND RABBITS, AND EX VIVO PIG ORGAN CULTURE. THIS DIRECT TO PHASE II SBIR PROJECT WILL ADVANCE SDUSP10 TOWARDS MARKET LAUNCH THROUGH EXPANSION OF EFFICACY STUDIES THAT WILL FOCUS ON PERSISTENCE EPITHELIAL DEFECT (PED) MODELS IN MICE AND RABBITS AND IN HUMAN CORNEAL ORGAN CULTURE. BASED ON COMPARABLE THERAPEUTICS IN THE OCULAR SPACE, THESE WILL CONTRIBUTE SIGNIFICANTLY TO THE ANIMAL EFFICACY STUDIES NEEDED BEFORE FIRST-IN-HUMAN TRIALS. IN PREPARATION FOR IND FILING, THE PROJECT WILL ALSO SUPPORT THE DEMONSTRATION OF SCALED-UP PRODUCTION OF HUMAN SDUSP10 IN A GLP ENVIRONMENT. THE PRODUCTION RUNS WILL BE USED TO CONDUCT IND-ENABLING STUDIES INCLUDING TOXICOLOGY AND PK EXPERIMENTS IN RABBITS. AT THE CONCLUSION OF THE PROJECT, DUB BIOLOGICS WILL HAVE COMPLETED ALL REQUIRED EFFICACY STUDIES, CREATED A SCALED- UP MANUFACTURING PROCESS THAT IS READY FOR CGMP CONVERSION, AND DEMONSTRATED THE SAFETY PROFILE OF SDUSP10. THIS WILL VALIDATE THE TECHNICAL VIABILITY OF PURSUING THIS THERAPEUTIC PIPELINE, ENABLING EXTERNAL INVESTMENT TO FUND THE REMAINING IND-ENABLING STUDIES AND CONDUCT EARLY-STAGE CLINICAL TRIALS. CREATING A WAY TO PREVENT PED AND CORNEAL SCARRING SAFELY AND EFFECTIVELY WILL IMPROVE THE QUALITY OF LIFE OF MILLIONS OF PATIENTS AROUND THE WORLD AND REDUCE THE ECONOMIC BURDEN OF CORNEAL OPACIFICATION AND DEMAND FOR CORNEAL TRANSPLANTS.