Project Grant F31NS151913

POLYMERSOME-MEDIATED NEUROLOGIC ENZYME REPLACEMENT THERAPY FOR THE TREATMENT OF GM1 GANGLIOSIDOSIS - ABSTRACT: GM1 GANGLIOSIDOSIS (GM1) IS A DEVASTATING FORM OF LYSOSOMAL STORAGE DISEASE (LSD) WITH NO CLINICALLY AVAILABLE TREATMENT. PATIENTS WITH GM1 ARE UNABLE TO CLEAR GLYCOSPHINGOLIPIDS, INCLUDING GM1 GANGLIOSIDE, DUE TO MISFOLDING OR LACK OF PRESENTATION OF THE ENZYME B- GALACTOSIDASE (BGAL). WHILE MANY LSDS ARE TREATABLE WITH EXOGENOUS ENZYME REPLACEMENT THERAPY (ERT), GM1 PRIMARILY AFFECTS NEURONS AND THEREFORE INTRODUCES THE CHALLENGING OBSTACLE OF THE BLOOD-BRAIN BARRIER (BBB). WE DEVELOPED SYNTHETIC POLYMER VESICLES KNOWN AS POLYMERSOMES TO ENCAPSULATE AND DELIVER BGAL ACROSS THE BBB. THESE POLYMERSOMES WERE COVALENTLY TAGGED WITH APOLIPOPROTEIN E (APOE), A NATURAL CHOLESTEROL TRANSPORTER PROTEIN THAT HAS BEEN STUDIED EXTENSIVELY FOR BRAIN TARGETING DUE TO ITS UPREGULATED RECEPTORS IN STATES OF INFLAMMATION SUCH AS THE NEUROINFLAMMATION OF GM1. MY PREVIOUS RESEARCH IN GM1 MOUSE MODELS HAS DEMONSTRATED THAT INTRAVENOUSLY INJECTED BGAL LOADED APOE POLYMERSOMES CROSS THE BBB AND RESTORE BGAL ENZYME ACTIVITY WITHIN THE BRAIN TO WILD-TYPE LEVELS. APOE FUNCTIONALIZED POLYMERSOMES SHOW AN AFFINITY FOR NEURONAL INTERNALIZATION AND ARE A PRIME CANDIDATE FOR CONTINUED DOSING STUDIES IN GM1. THEREFORE, I AIM TO UTILIZE OUR BGAL DELIVERY PLATFORM IN A DOSING REGIMEN TO MAINTAIN ENZYME ACTIVITY AND CLEARANCE IN THE BRAINS OF GM1- AFFECTED MICE. THIS WILL ULTIMATELY DETERMINE THE OPTIMAL ADMINISTRATION WINDOW FOR CONTINUED CLEARANCE AND CONTRIBUTE TO THE INVESTIGATION OF THE LONG-TERM SAFETY OF MULTIPLE ADMINISTRATIONS OF THIS NANOPARTICLE ERT PLATFORM (NANODIVERT). FURTHERMORE, I INTEND TO LEVERAGE THE EFFECTIVE MODELING DEMONSTRATED BY PATIENT-DERIVED HUMAN GM1-AFFECTED ORGANOIDS TO ANALYZE HOW NANODIVERT INTERACTS WITH HUMAN NEUROLOGIC CELLS THAT MORE CLOSELY RECAPITULATE THE DISEASE. UTILIZING A 3D NEUROLOGICAL ARCHITECTURE OF GM1 CELLS PROVIDES DIRECT INSIGHT INTO LYSOSOMAL TRAFFICKING, THERAPEUTIC RECOVERY OF ENZYME ACTIVITY, AND SECRETION OF ENZYMES TO OTHER ENZYME- DEFICIENT CELLS, KNOWN AS CROSS-CORRECTION. SIMULTANEOUSLY, I WILL ANALYZE THE IMMUNE RESPONSE THAT IS MORE SPECIFIC TO PATIENTS. THESE AIMS CULMINATE IN PRODUCING A TRANSLATIONAL, MECHANISTIC, AND RIGOROUSLY VALIDATED ERT FOR GM1 GANGLIOSIDOSIS. PATIENTS WITH GM1 GANGLIOSIDOSIS CURRENTLY HAVE NO CLINICALLY AVAILABLE TREATMENTS, AND ALTHOUGH SOME CLINICAL TRIALS USING VIRAL TREATMENTS HAVE SHOWN PROMISING DELAYS IN MORTALITY, THIS ORPHAN DISEASE ALWAYS RESULTS IN DEATH IN THE INFANTILE AND JUVENILE FORMS OF THE DISEASE. THE URGENCY FOR THE DEVELOPMENT OF NEW TREATMENTS FOR THIS DEVASTATING DISEASE, PARTICULARLY THE OPTIMIZATION OF ERTS CAPABLE OF BYPASSING THE BBB, AS PROPOSED HERE.