IDENTIFICATION OF POTENTIAL BIOMARKERS AND CLINICAL TOOLS FOR USE IN MUCOPOLYSACCHARIDOSIS IIIC PATIENTS. - PROJECT SUMMARY/ABSTRACT LYSOSOMAL STORAGE DISEASES (LSD) ARE RARE INHERITED METABOLIC DISORDERS CAUSED BY DEFECTS IN THE CELLULAR CATABOLIC SYSTEM. MUCOPOLYSACCHARIDOSIS TYPE IIIC (MPS IIIC OR SANFILIPPO DISEASE TYPE C) IS ONE SUCH LSD THAT IS CAUSED BY DEFICIENCY OF THE ENZYME HEPARAN SULFATE ACETYL COA: -GLUCOSAMINIDE N-ACETYLTRANSFERASE, (HGSNAT) ESSENTIAL FOR DEGRADATION OF HEPARAN SULFATE, A REPEATING CARBOHYDRATE GENERALLY FOUND ATTACHED TO PROTEOGLYCANS. THIS DISEASE CAUSES ACCUMULATION OF HEPARAN SULFATE RESULTING IN A PROGRESSIVE AND SEVERE NEUROLOGICAL DETERIORATION EARLY IN LIFE WITH LITTLE SOMATIC FEATURES. THE SYMPTOMS IN PATIENTS WITH MPS IIIC MAY PRESENT AT AN AVERAGE AGE OF 3.5 YEARS OF AGE WITH PSYCHOMOTOR DEVELOPMENTAL DELAYS AND BEHAVIORAL PROBLEMS. BEFORE THE AGE OF 15 YEARS VERBAL COMMUNICATION IS OFTEN LOST IN PATIENTS WITH MPS IIIC. MOST LOSE THE ABILITY TO WALK BETWEEN THE 20 AND 30 YEARS OF AGE. THE CONDITION IS FATAL BY AN AVERAGE AGE OF 34 YEARS (RANGE, 25-48). ENZYME REPLACEMENT THERAPIES ARE NOT AN OPTION SINCE THE PROTEIN IS LOCALIZED AND BOUND TO LYSOSOMAL MEMBRANE. THERE ARE CURRENTLY NO TREATMENTS AVAILABLE FOR TREATMENT OF MPS IIIC. INDIVIDUALS AFFECTED BY MPS IIIC ARE MANAGED WITH SUPPORTIVE CARE, CONSULTATION WITH MEDICAL PROFESSIONALS FROM MULTIPLE DISCIPLINES, PHYSICAL THERAPY, AND PHARMACOLOGICAL INTERVENTIONS TO ALLEVIATE SYMPTOMS. GENE THERAPY REPRESENTS A REASONABLE AND PROMISING APPROACH TO PROVIDE A MEANINGFUL AND LONG-TERM THERAPEUTIC BENEFIT FOR THIS POPULATION IN THE NEAR FUTURE. WE HAD A POSITIVE INTERACTION WITH THE FDA AND GOT GUIDANCE FOR MOVING OUR PROGRAM INTO THE CLINICS. IN PREPARATION FOR THE INTERVENTIONAL STUDY THE RECOMMENDATION WAS FOR A THOROUGH NATURAL HISTORY STUDY (NHS) IN THE AVAILABLE PATIENT POPULATION WITH A BROAD NET TO CAPTURE ENDPOINTS THAT ARE MOST LIKELY TO PREDICT THE CLINICAL BENEFITS IN INDIVIDUALS. SINCE THE NUMBER OF DIAGNOSED PATIENTS IS SMALL, INDIVIDUALS COULD POTENTIALLY SERVE AS THEIR OWN CONTROL AT THE TIME OF INTERVENTION, WHERE THE PATIENT WILL RECEIVE THE GENE THERAPY. MOST OF THE WORK WILL BE EXECUTED BY CONTRACTED SERVICE PROVIDERS. THE CLINICAL TRIAL ITSELF WILL BE CONDUCTED AT UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX. THE CLINICAL PROTOCOL WAS DESIGNED BY THE TEAM AT PHOENIX NEST WITH HELP OF KOLS AND CLINICAL EXPERTS IN THE MPS III FIELD. WE HAVE ENGAGED EXPERT THIRD PARTY CLINICAL SERVICE PROVIDERS TO HELP WITH THE EXECUTION, MONITORING AND DATA COLLECTION. CRUCIAL DATA COLLECTED FROM THE PATIENTS ON THIS STUDY WILL HELP US DEVELOP CLINICAL OUTCOMES THAT WILL BE TOOLS FOR MEASURING THE EFFICACY OF OUR AAV9 GENE THERAPY. THIS TRIAL WILL PUT A STEP CLOSER TO EXECUTING THE PIVOTAL TRIAL TO ASSESS THE EFFICACY OF OUR EXPERIMENTAL THERAPY AND ITS COMMERCIALIZATION.