SBIR-STTR Award

The studies proposed in this application will test the feasibility of treating mucopolysaccharidosis (MPS) through a novel therapeutic approach called Substrate Optimization Therapy (SOT). MPS is a family of lysosomal storage diseases caused by mutations in the enzymes that normally degrade glycosaminoglycans (GAGs). Because of deficiencies in the mutated enzymes, GAGs build up to toxic levels causing a wide range of symptoms including severe mental retardation, cardiac dysfunction, and early death. Current therapies attempt to compensate for the deficiencies by IV infusion of specific recombinant enzymes, Enzyme Replacement Therapy (ERT). Patients, especially those only mildly affected, do receive some benefit from ERT, however the benefit is limited primary because of minimal penetration of infused enzymes in tissues with restricted blood flow such as joints (synovial capsule), heart valve (cartilage), and brain (blood brain barrier). Further, many patients rapidly develop blocking antibody responses to ERT, an effect that is most pronounced in those patients that are most severely affected. Substrate Optimization Therapy is novel because it uses the first ever small molecule GAG biosynthesis inhibitors to subtlety shape the fine structural composition of GAGs in patients, enabling the GAGs to be degraded despite the pathogenic enzyme deficiency. The small molecule approach is superior because it can penetrate the relevant tissues including the central nervous system, heart valve, bone, and joints plus it avoids issues of antibody inhibition in those patients most in need of treatment. Also, due to the underlying biology and disease pathogenesis, this approach will treat both MPS I and MPS II with a single therapeutic agent. Through the studies proposed in this application, we will identify the best small molecule SOT agents for a proof of concept efficacy study in the mouse model of MPS II.

Public Health Relevance:
Relevance The goal of this proposal is to test the feasibility of a novel therapeutic approach to treating mucopolysaccharidosis II (MPS II). MPS II is a rare genetic disease that is currently only partially managed through weekly intravenous injections. Through this grant we aim to identify compounds that are the crucial starting point for the development of the first orally available CNS penetrant therapy for this devastating disease.

Thesaurus Terms:
Affect; Anabolism; Antibodies; Antibody Formation; Antibody Production; Antibody Response; Articular Capsule; Articulation; Assay; Bioassay; Biologic Assays; Biological Assay; Biology; Blocking Antibodies; Blood - Brain Barrier Anatomy; Blood Flow; Blood-Brain Barrier; Body Tissues; Bone; Bone And Bones; Bones And Bone Tissue; Brain; Capsula Articularis; Cardiac; Cardiac Valves; Cartilage; Cartilagenous Tissue; Central Nervous System; Cessation Of Life; Characteristics; Death; Development; Disease; Disorder; Drip Infusions; Drip, Intravenous; Dysfunction; Ec 2.8.2; Encephalon; Encephalons; Enzymes; Family; Functional Disorder; Gargoylism, Hunter Syndrome; Genetic Condition; Genetic Diseases; Glycobiology; Glycosaminoglycans; Goals; Grant; Heart Valves; Hemato-Encephalic Barrier; Hereditary Disease; Hunter Syndrome Gargoylisms; Hunter Syndrome; Hunter's Syndrome; Hunter-Fraser Syndrome; Hunter-Mcalpine Syndrome; Iv Infusion; Infusions, Intravenous; Intravenous Infusion Procedures; Joint Capsule; Joints; Lysosomal Enzyme Disorders; Lysosomal Storage Diseases; Mps 1; Mps I; Mps I S; Mps Ii; Mps Type I S; Mammals, Mice; Mental Retardation; Metabolic; Mice; Modeling; Molecular Disease; Mucopolysaccharides; Mucopolysaccharidoses; Mucopolysaccharidosis; Mucopolysaccharidosis 1; Mucopolysaccharidosis 2; Mucopolysaccharidosis I; Mucopolysaccharidosis I S; Mucopolysaccharidosis Ii; Mucopolysaccharidosis Is; Murine; Mus; Mutate; Nervous System, Brain; Nervous System, Cns; Neuraxis; Pathogenesis; Patients; Penetration; Phase; Physiopathology; Programs (Pt); Programs [publication Type]; Property; Property, Loinc Axis 2; Protein Replacement Therapy; Recombinants; Shapes; Structure-Activity Relationship; Symptoms; Syndrome, Scheie's; Synovial Capsule; Technology; Testing; Therapeutic Agents; Tissues; X-Linked Hurler Syndrome; Alpha-L-Iduronidase (Ida, Idua) Deficiency; Alpha-L-Iduronidase Deficiency; Analog; Antibody Biosynthesis; Base; Biosynthesis; Bone; Chemical Structure Function; Disease-Causing Mutation; Disease/Disorder; Drug Development; Efficacy Testing; Enzyme Deficiency; Enzyme Replacement Therapy; Genetic Disorder; Hereditary Disorder; Iduronate Sulfatase (Ids) Deficiency; Iduronate Sulfatase Deficiency; Iduronate-2-Sulfatase Deficiency; Iduronidase Deficiency Disease; Immunoglobulin Biosynthesis; In Vitro Model; In Vivo; Inborn Lysosomal Enzyme Disorder; Inhibitor; Inhibitor/Antagonist; Innovate; Innovation; Innovative; Intravenous Injection; Mouse Model; Mucopolysaccharide Storage Disease I; Mucopolysaccharide Storage Disease Ii; Mucopolysaccharidosis (Mps) I; Mucopolysaccharidosis (Mps) Ii; Mucopolysaccharidosis Type I; Mucopolysaccharidosis Type Ii; Novel; Novel Therapeutic Intervention; Pathophysiology; Prevent; Preventing; Programs; Public Health Relevance; Scaffold; Scaffolding; Small Molecule; Structure Function Relationship; Sulfo-Iduronate Sulfatase (Sids) Deficiency; Sulfo-Iduronate Sulfatase Deficiency; Sulfotransferase

The studies proposed in this application are aimed at progressing an innovative approach to treating mucopolysaccharidoses (MPS) toward clinical trials. MPS is a family of lysosomal storage diseases caused by mutations in the enzymes that normally degrade glycosaminoglycans (GAGs). Because of deficiencies in the mutated enzymes, GAGs build up to toxic levels causing a wide range of symptoms including severe mental retardation, cardiac dysfunction, and early death. Current therapies attempt to compensate for the deficiencies by IV infusion of specific recombinant enzymes, Enzyme Replacement Therapy (ERT). Patients, especially those only mildly affected, do receive some benefit from ERT, however the benefit is limited primary because of minimal penetration of infused enzymes in tissues with restricted blood flow such as joints (synovial capsule), heart valve (cartilage), and brain (blood brain barrier). Further, many patients rapidly develop blocking antibody responses to ERT, an effect that is most pronounced in those patients that are most severely affected. Our therapeutic approach (Substrate Optimization Therapy, SOT) is novel because it uses the first ever small molecule GAG biosynthesis inhibitors to subtlety shape the fine structural composition of GAGs in patients, enabling the GAGs to be degraded despite the pathogenic enzyme deficiency. The small molecule approach is superior because it can penetrate the relevant tissues including the central nervous system, heart valve, bone, and joints plus it avoids issues of antibody inhibition in those patients most in need of treatment. Also, due to the underlying biology and disease pathogenesis, this approach will treat MPS I, II, and III with a single therapeutic agent. Through the studies proposed in this application, we will complete the preclinical and IND enabling studies required to initiate a Phase I clinical trial.

Public Health Relevance:
Relevance The goal of this proposal is to develop a new therapy for treating mucopolysaccharidosis (MPS). MPS is a collection of rare childhood genetic diseases that are currently only partially managed through weekly intravenous injections that do not treat the neurological deficits arising from the diseases. Through this grant we aim to develop the first therapy to treat all symptoms including the devastating neurological deficits of these diseases.

Thesaurus Terms:
Absorption;Address;Affect;Anabolism;Antibodies;Antibody Formation;Antibody Production;Antibody Response;Articular Capsule;Articulation;Assay;Bioassay;Bioavailability;Biologic Assays;Biologic Availability;Biological Assay;Biological Availability;Biology;Blocking Antibodies;Blood - Brain Barrier Anatomy;Blood Flow;Blood-Brain Barrier;Body Tissues;Bone;Bone And Bones;Bones And Bone Tissue;Brain;Capsula Articularis;Carbohydrates;Cardiac;Cardiac Valves;Cartilage;Cartilagenous Tissue;Cells;Central Nervous System;Cessation Of Life;Chemistry;Chemistry, Pharmaceutical;Childhood;Chronic;Clinical;Clinical Research;Clinical Study;Clinical Trials;Clinical Trials, Phase I;Clinical Trials, Unspecified;Collection;Controlled Study;Death;Development;Development And Research;Disease;Disorder;Drip Infusions;Drip, Intravenous;Drug Kinetics;Drugs;Drugs, Investigational;Dysfunction;Early-Stage Clinical Trials;Elements;Encephalon;Encephalons;Enzymes;Excretory Function;Family;Foundations;Functional Disorder;Funding;Genetic Condition;Genetic Diseases;Glycosaminoglycans;Goals;Grant;Heart Valves;Hemato-Encephalic Barrier;Hereditary Disease;High Throughput Assay;Iv Infusion;In Vitro;Infusions, Intravenous;Intermediary Metabolism;Intravenous Infusion Procedures;Investigational Drugs;Investigational New Drug Application;Investigational New Drugs;Investments;Joint Capsule;Joints;Lead;Letters;Lysosomal Enzyme Disorders;Lysosomal Storage Diseases;Metbl;Mps 1;Mps I;Mps I S;Mps Type I S;Mammals, Mice;Medication;Medicinal Chemistry;Mental Retardation;Metabolic Processes;Metabolism;Mice;Modeling;Molecular Disease;Morbidity;Morbidity - Disease Rate;Mucopolysaccharides;Mucopolysaccharidoses;Mucopolysaccharidosis;Mucopolysaccharidosis 1;Mucopolysaccharidosis I;Mucopolysaccharidosis I S;Mucopolysaccharidosis Is;Murine;Mus;Mutate;Nerve Degeneration;Nervous System, Brain;Nervous System, Cns;Neuraxis;Neurologic;Neurological;Neuron Degeneration;Oral;Pathogenesis;Patients;Pb Element;Penetration;Performance;Pharmaceutic Chemistry;Pharmaceutic Preparations;Pharmaceutical Agent;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmaceuticals;Pharmacokinetics;Pharmacologic Substance;Pharmacological Substance;Phase;Phase 1 Clinical Trials;Phase I Clinical Trials;Phase I Study;Physiologic Availability;Physiopathology;Preparation;Process;Process Of Absorption;Production;Programs (Pt);Programs [publication Type];Property;Property, Loinc Axis 2;Protein Replacement Therapy;R &D;R&D;Recombinants;Research;Sbir;Sbirs (R43/44);Safety;Science Of Chemistry;Series;Shapes;Small Business Innovation Research;Small Business Innovation Research Grant;Symptoms;Syndrome, Scheie's;Synovial Capsule;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Toxicology;Absorption;Alpha-L-Iduronidase (Ida, Idua) Deficiency;Alpha-L-Iduronidase Deficiency;Analog;Antibody;Antibody Biosynthesis;Base;Bioavailability Of Drug;Biosynthesis;Blocking Antibody;Blood Brain Barrier;Bone;Brain Tissue;Carbohydrate Biosynthesis;Carbohydrate Structure;Clinical Investigation;Clinical Trial Phase I;Commercialization;Disease /Disorder;Disease-Causing Mutation;Disease/Disorder;Drug /Agent;Drug Discovery;Drug/Agent;Enzyme Deficiency;Enzyme Replacement Therapy;Excretion;Genetic Disorder;Heavy Metal Pb;Heavy Metal Lead;Hereditary Disorder;High Throughput Screening;Iduronidase Deficiency Disease;Immunoglobulin Biosynthesis;Improved;In Vivo;Inborn Lysosomal Enzyme Disorder;Inhibitor;Inhibitor /Antagonist;Inhibitor/Antagonist;Innovate;Innovation;Innovative;Interest;Intravenous Injection;Meetings;Model;Mucopolysaccharide Storage Disease I;Mucopolysaccharidosis (Mps) I;Mucopolysaccharidosis Type I;Neural Degeneration;Neurodegeneration;Neuronal Degeneration;Novel;Pathophysiology;Pediatric;Phase 1 Study;Phase 1 Trial;Phase I Trial;Pre-Clinical;Preclinical;Premature;Programs;Protocol, Phase I;Research And Development;Small Molecule