Using a novel high-throughput screening approach, we have recently identified the first selective small molecule inhibitors of the biosynthesis of gangliosides. The proposed funding will enable important preclinical development activities required to advance these promising compounds as a novel therapy for the GM2 gangliosidoses. GM2 gangliosidosis is a family of genetic diseases including Tay-Sachs, Sandhoff, and the AB variant that are caused by mutations in subunits of the enzyme complex required to degrade gangliosides. Due to the lysosomal enzyme deficiency, gangliosides build up to toxic levels leading to severe neurological decline and death. The ganglioside biosynthetic inhibitors would be expected to alleviate disease severity through a substrate reduction mechanism by selectively restricting the ganglioside flux through the compromised lysosomal degradative system. We will test if these compounds can reduce lysosomal ganglioside accumulation in fibroblasts from patients with GM2 gangliosidosis. Active scaffolds will then be tested for important physiochemical, pharmacological and medicinal chemistry properties to identify the most promising scaffolds for further development. When completed, these studies will lay the foundation for additional preclinical development of the first therapy for these devastating diseases.
Public Health Relevance: Relevance The goal of this proposal is to complete important early-stage product development activities for a new therapy to treat two related and devastating diseases: Tay-Sachs and Sandhoff diseases. These genetically-induced diseases are present from birth and lead to severe neurological damage and premature death. No effective treatments exist for these conditions. As a result, the proposed research has the potential to enable the first effective treatment for two devastating, childhood diseases associated with significant morbidity and mortality.
Thesaurus Terms: Assay;Behavior;Bioassay;Biologic Assays;Biological Assay;Birth;Boxing;Caffey Pseudo-Hurler Syndrome;Caffey Syndrome;Cell Culture Techniques;Cells;Ceramide Glucosyltransferase;Cessation Of Life;Characteristics;Chemistry, Pharmaceutical;Childhood;Collection;Death;Development;Disease;Disorder;Drug Kinetics;Drugs;Enzymes;Fibroblasts;Foundations;Funding;Future;G(M1) Gangliosidosis;G(M2) Gangliosidoses;Gm2 Gangliosidosis, Type I;Gm2 Gangliosidosis, Type Ii;Ganglioside Biosynthesis;Ganglioside Biosynthesis Pathway;Ganglioside Storage Diseases;Ganglioside Storage Disorders;Gangliosides;Gangliosidoses;Gangliosidoses Gm2;Gangliosidosis G(M2), Type I;Gangliosidosis G(M2), Type Ii;Gangliosidosis Gm1;Genetic Alteration;Genetic Change;Genetic Condition;Genetic Diseases;Genetic Defect;Glccer Synthase;Glucocerebrosides;Glucosyl Ceramides;Glucosylceramides;Glycans;Glycolipids;Goals;Hereditary Disease;Hexosaminidase A Deficiency Disease;Hexosaminidase A And B Deficiency Disease;High Throughput Assay;Hurler Variant;Hurler-Like Syndrome;Ic50;In Vitro;Inhibitory Concentration 50;Intervention;Intervention Strategies;Landing Syndrome;Lead;Link;Lipids;Lysosomal Enzyme Disorders;Lysosomal Storage Diseases;Measures;Medication;Medicinal Chemistry;Metabolic;Modeling;Molecular Disease;Morbidity;Morbidity - Disease Rate;Mortality;Mortality Vital Statistics;Multienzyme Complexes;Mutation;Nervous System Injuries;Nervous System Trauma;Nervous System Damage;Neurologic;Neurological;Neurological Damage;Neurological Injury;Neurological Trauma;Norman-Landing Syndrome;Orphan Disease;Parturition;Pathway Interactions;Patients;Pb Element;Penetration;Pharmaceutic Chemistry;Pharmaceutic Preparations;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacokinetics;Pharmacology;Phase;Polysaccharides;Probability;Programs (Pt);Programs [publication Type];Property;Property, Loinc Axis 2;Research;Risk;Sbir;Sbirs (R43/44);Sandhoff Disease;Sandhoff Jatzkewitz Disease;Sandhoffs Disease;Series;Severity Of Illness;Sialoglycosphingolipids;Small Business Innovation Research;Small Business Innovation Research Grant;Solubility;Solutions;Staging;System;System, Loinc Axis 4;Tay Sachs Disease;Tay-Sachs Disease;Tay-Sachs Disease With Visceral Involvement;Testing;Toxic Effect;Toxicities;Trauma, Nervous System;Udp-Glucose-N-Acylsphingosine Glucosyltransferase;Udp-Glucose-Ceramide Glucosyltransferase;Udpglucose-Ceramide Glucosyltransferase;Variant;Variation;Work;Analog;Base;Beta Galactosidase Deficiency;Beta-Galactosidase-1 (Glb1) Deficiency;Beta-Galactosidase-1 Deficiency;Ceramide Udpg Glucosyltransferase;Cerebral Gm1 Gangliosidosis;Cerebroside Synthase;Cost;Design;Designing;Disease /Disorder;Disease Severity;Disease/Disorder;Drug /Agent;Drug/Agent;Effective Therapy;Enzyme Complex;Enzyme Deficiency;Familial Neurovisceral Lipidosis;Family Genetics;Gagliosidosis Gm1, Type I;Gangliosidosis;Generalized Gangliosidosis Gm1, Type I;Generalized Infantile Gangliosidosis;Generalized Infantile Gangliosidosis With Bony Involvement;Genetic Disorder;Genome Mutation;Glucocerebroside Synthetase;Glucosylceramide Synthase;Glycosylceramide Synthetase;Heavy Metal Pb;Heavy Metal Lead;Hereditary Disorder;Hexosaminidase A Deficiency;Hexosaminidase A And B Deficiency;High Risk;High Throughput Screening;In Vitro Model;In Vivo;Inborn Lysosomal Enzyme Disorder;Inhibitor;Inhibitor /Antagonist;Inhibitor/Antagonist;Interventional Strategy;Model;Neuronal Gm(1) Gangliosidosis;Neurovisceral Lipidosis;Novel;Pathway;Pediatric;Pre-Clinical;Preclinical;Premature;Product Development;Programs;Pseudo-Hurler Disease;Scaffold;Scaffolding;Small Molecule;Success
