Project Grant R44NS129393

DEVELOPMENT OF GENE REPLACEMENT THERAPY FOR SANFILIPPO SYNDROME TYPE C - 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. THE GOAL OF THIS SBIR PROJECT IS TO COMPLETE TISSUE LEVEL ASSESSMENTS IN THE DISEASE MODEL, SCALE UP MANUFACTURING AND ESTABLISH SAFETY ON A GLP REGULATED STUDY IN RATS. THESE ACTIVITIES WILL HELP BUILD A ROBUST BRIEFING PACKAGE FOR IND-FILING FOR OUR GENE THERAPY PRODUCT, JLK-247. THE PROGRESS WILL HELP US NAVIGATE THE "VALLEY OF DEATH" BY ESTABLISHING MILESTONES AND MAKING GO/NO-GO DECISIONS. THE SAFE THERAPEUTIC DOSE-RANGE ESTABLISHED WILL HELP US EXTRAPOLATE AND TRANSLATE THERAPEUTIC DOSES TO CLINICAL PHASE I TRIALS. THIS PROPOSAL LEVERAGES THE SCIENTIFIC EXPERTISE IN GENE THERAPY PRECLINICAL DEVELOPMENT AND REGULATORY EXPERIENCE OF SRIKANTH SINGAMSETTY, PHD (PHOENIX NEST, INC.) FOR THE PRODUCT DEVELOPMENT. JILL WOOD, BS (PHOENIX NEST, INC.), WILL MANAGE THE PROJECT FINANCES AND PERSONNEL RESPONSIBLE. PROFESSOR STEVEN GRAY, PHD (THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, DALLAS, TX) IS OUR GENE THERAPY SUBJECT MATTER EXPERT. SUCCESSFUL COMPLETION OF THIS PROJECT WILL HELP WITH INITIATING CLINICAL TRIAL DOSING, A FIRST STEP TOWARDS A LONG-TERM THERAPY FOR MPSIIC, A DREADFUL AND FATAL PEDIATRIC DISEASE.