Grace Science Foundation

THE MISSION OF THE FOUNDATION IS TO SUPPORT AND FUND THE DEVELOPMENT OF LIFE-SAVING TREATMENT FOR

STANFORD UNIVERSITY NGLY1 NATURAL HISTORY STUDY (MAURA RUZHNIKOV) TEAM CONTINUES A NATURAL HISTORY STUDY TO DEFINE THE CLINICAL SPECTRUM OF THE DISEASE AND ITS PROGRESSION, AND DEFINE BIOMARKER ENDPOINTS FOR USE IN THERAPEUTIC TRIALS. THIS STUDY IS LED BY DR. MAURA RUZHNIKOV, MD, A CHILD NEUROLOGIST AND MEDICAL GENETICIST FOCUSING ON THE DIAGNOSIS AND MANAGEMENT OF RARE NEUROLOGIC DISORDERS, INCLUDING GENETIC EPILEPSY SYNDROMES, CHILDHOOD NEURODEGENERATIVE DISEASES, AND UNDIAGNOSED SUSPECTED GENETIC CONDITIONS. AS OF THE END OF 2021, THE STUDY HAS COLLECTED DATA FROM MORE THAN TWENTY-NINE PATIENTS BOTH ON-SITE AND REMOTE. THE STUDY HAS CHARACTERIZED DEVELOPMENT DELAY, MOVEMENT SYMPTOMS, PATIENT QUALITY OF LIFE, EPILEPSY PHENOTYPES, AND HAS HELPED ESTABLISH A BIOMARKER THAT IS UNIVERSALLY ELEVATED IN PATIENTS, PROVIDING A POTENTIAL TOOL TO ADVANCE THERAPY DEVELOPMENT. THE STUDY HAS FOLLOWED PARTICIPANTS LONGITUDINALLY OVER THREE YEARS.

UNIVERSITY OF TEXAS SOUTHWESTERN (YAN LAB) TEAM HAS BEEN GENERATING AND CHARACTERIZING SEVERAL MOUSE MODELS OF NGLY1 DEFICIENCY, INCLUDING MODELS IN WHICH THE GENE IS INACTIVATED IN CERTAIN TISSUES AND CONDITIONALLY AFTER BIRTH. THESE MOUSE MODELS HAVE ALLOWED THEM TO CHARACTERIZE NEUROLOGICAL PHENOTYPES, NEUROPATHOLOGICAL CHANGES, INFLAMMATION, SENSORY AND MOTOR DEFECTS, AND DISEASE ASSOCIATED BIOMARKERS. THESE ANIMAL MODELS PROVIDE INSIGHTS INTO THE SPECIFIC DEFECTS THAT RESULT FROM NGLY1 LOSS AND ESTABLISH A FOUNDATION FOR TESTING CANDIDATE THERAPIES, INCLUDING GENE THERAPIES AND SMALL MOLECULE DRUGS. THE TEAM HAS ALSO FOUND THAT NGLY1 DEFICIENCY IN MICE TRIGGERS A SPECIFIC INNATE IMMUNE PATHWAY MEDIATED BY THE CGAS/STING PATHWAY. USING GENETIC AND PHARMACOLOGICAL APPROACHES, THE TEAM HAS UNCOVERED THREE DIFFERENT TARGETS THAT CAN BE MODULATED TO REDUCE DISEASE ASSOCIATED PHENOTYPES AND IMPROVE SURVIVAL.

THE NEW YORK STEM CELL FOUNDATION (NYSCF) TEAM HAS DEVELOPED AND VALIDATED FOUR ADDITIONAL PATIENT-DERIVED INDUCED PLURIPOTENT STEM CELL (IPSC) LINES TO COMPLEMENT AND EXPAND HUMAN CELL MODELS OF NGLY1 DEFICIENCY. CRISPR-MEDIATED GENOME EDITING WAS USED TO PRODUCE ISOGENIC CONTROL LINES TO ESTABLISH DISEASE-SPECIFIC CHARACTERISTICS. TEAM HAS FURTHER USED THESE IPSC LINES TO GENERATE HUMAN NEURONAL MODELS OF NGLY1 DEFICIENCY AND HAS BEGUN TO CHARACTERIZE NGLY1-DEPENDENT NEURONAL PHENOTYPES INCLUDING CHANGES IN CELLULAR ARCHITECTURE, MITOCHONDRIAL FUNCTION, INTRACELLULAR AGGREGATES, NEURONAL ACTIVITY, AND PATTERNS OF GENE EXPRESSION. THESE MODELS WILL BE LEVERAGED FOR TESTING POTENTIAL THERAPIES TO REVERSE PATHOLOGIES ASSOCIATED WITH NGLY1 DEFICIENCY.