Project Grant R43AR084638

CELL-BASED GENE THERAPY FOR MPS IVA - PROJECT SUMMARY/ABSTRACT MUCOPOLYSACCHARIDOSIS TYPE IVA (MORQUIO A OR MPS IVA) IS A RARE AUTOSOMAL RECESSIVE LYSOSOMAL STORAGE DISEASE WITH A PREVALENCE OF ~1/250,000 PEOPLE IN THE US. IT IS CAUSED BY FAULTY GENETIC ENCODING FOR N-ACETYLGAL- ACTOSAMINE-6-SULFATE SULFATASE (GALNS), AN ENZYME THAT HYDROLYZES THE GLYCOSAMINOGLYCANS, CHONDROITIN-6- SULFATE AND KERATAN SULFATE. DEFICIENCY OF GALNS LEADS TO ACCUMULATION OF THE SUBSTRATES IN CARTILAGE, BONES, AND ORGANS, COMPROMISING THE TISSUES AND THEIR FUNCTION AND CAUSING ABNORMAL JOINT HYPERFLEXIBILITY AND WEAKNESS, WIDESPREAD BONE DYSPLASIA, STUNTED GROWTH, AND ORGAN COMPLICATIONS. CURRENT THERAPIES INCLUDE INVASIVE ORTHOPEDIC SURGERIES, ENZYME REPLACEMENT THERAPY (ERT; FDA APPROVED 2014), AND HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT), WHICH HAS BEEN PERFORMED MORE FREQUENTLY IN SOME OTHER MPS VARIANTS. SURGERIES PERFORMED IN MANY MPS IVA PATIENTS INCLUDE VERTEBRAL DECOMPRESSION AND FUSION, HIP RECONSTRUCTION, AND LARYNGOTOMY. THE NEED FOR ONGOING SURGERIES AND ASSOCIATED COMPLICATIONS OFTEN REDUCE PATIENT QUALITY OF LIFE, AND TOTAL MOBILITY LOSS CAN OCCUR, REQUIRING A WHEELCHAIR. ERT HAS MILD TO MODERATE BENEFITS ON ORGANS AND FUNCTIONAL ENDURANCE, BUT IT DOES NOT IMPROVE DEGENERATIVE SKELETAL AND CARTILAGINOUS EFFECTS OF THE DISEASE. HSCT HAS BEEN USED FOR A LIMITED NUMBER OF MPS IVA PATIENTS, AND ALTHOUGH RESULTS SHOW IT CAN PRODUCE NORMAL ENZYME LEVELS IN THE BLOOD AND HAS SOME PREVENTATIVE EFFECT ON SKELETAL DEGENERATION, IT LACKS CURATIVE POWER AND IS NOT USUALLY RECOMMENDED. CLINICAL DATA SUPPORT OUR PREMISE THAT THE CONTINUOUS CELL-BASED DELIVERY OF SUPRAPHYSIOLOGIC LEVELS OF HUMAN GALNS COULD DRAMATICALLY IMPROVE PATIENT OUTCOMES. THE LONG-TERM GOAL OF THIS PROJECT IS TO DEVELOP AN ALLOGENEIC CELL-BASED GT PRODUCT THAT WILL NOT REQUIRE THE EXPENSIVE PROCEDURE OF AUTOLOGOUS CELL ISOLATION AND MODIFICATION, IMMUNOSUPPRESSION, I.E. CHEMOTHERAPY, AND THAT WILL HAVE A GOOD SAFETY PROFILE, BE RELATIVELY CONVENIENT, ACCESSIBLE TO A WIDE RANGE OF AGE GROUPS, AND ELIMINATE THE NEED FOR INVASIVE SURGERIES BY DELIVERY OF SUPRAPHYSIOLOGIC LEVELS OF GALNS. CURRENT THERAPIES ARE NOT CURATIVE BECAUSE OF DELIVERY OF INSUFFICIENT LEVELS OF GALNS, PARTICULARLY TO THE NOTORIOUSLY HARD-TO-REACH SKELETAL AND CARTILAGINOUS TISSUES CRITICALLY AFFECTED BY THE DISEASE. THE GOAL OF PHASE I IS TO OBTAIN EVIDENCE OF THE FEASIBILITY AND EFFICACY OF THE CELL-BASED GT SYSTEM TO SYSTEMICALLY DELIVER A CONTINUOUS HIGH DOSE OF THE ENZYME. THERE ARE TWO SPECIFIC AIMS. AIM 1 IS FOCUSED ON PRODUCING, OPTIMIZING, AND ANALYZING THE CHARACTERISTICS OF THE GENETICALLY-MODIFIED CELLS IN VITRO. IN AIM 2, WE WILL TEST THE THERAPEUTIC EFFICACY OF THE CONTINUOUS CELL-BASED DELIVERY OF THE RECOMBINANT HUMAN GALNS IN A MURINE MODEL OF MPS IVA THAT IS ENGINEERED TO ENGENDER TOLERANCE TO HUMAN GALNS AND TO LACK ENDOGENOUS MURINE GALNS ACTIVITY. IN PHASE II, WE WILL TEST EFFICACY IN ANOTHER MPS IVA ANIMAL MODEL AND COMPARE STRATEGIES TO PREVENT OR CONTROL THE TUMORIGENICITY OF IMPLANTED CELLS. A MAJOR FOCUS WILL BE PERFORMING STUDIES IN PREPARATION FOR APPLYING FOR INVESTIGATIONAL NEW DRUG (IND) STATUS FROM THE FDA.