GM1 gangliosidosis is lysosomal storage disease in which a key hydrolase enzyme, known as beta- galactosidase is missing in the lysosome resulting in the toxic accumulation of complex sugars called gangliosides, in particular GM1 and GA1 principally in the central nervous system. There is currently no cure or effective treatment available. A primary approach for treating related types of disorders involves replacement of the missing enzyme by injection into the circulation. Although intravenous enzyme replacement therapy (ERT) resolves many aspects of the disease, unfortunately it does not resolve complications of the disease in the CNS. Although, ERT is not a cure for this disease it can have a marked effect on the patient's development and thus quality of life. Intravenous ERT has been successfully commercialized for lysosomal mucopolysaccharidoses (MPS) disorders with approved drugs on the market, including (i) Laronidase for MPS I (Aldurazyme®, alpha-iduronidase, Hurler Syndrome), (ii) Idursulfatase for MPS II (Elaprase®, iduronate-2- sulfatase, Hunter Syndrome) and (iii) Vestronidase alfa for MPS VII (Mepsevii, beta-glucuronidase, Sly Syndrome). Intracerebroventricular (ICV) ERT has also been successfully commercialized for a progressive neurodegenerative lysosomal disease called Batten disease. Cerliponase Alfa (Brineura®, tripeptidyl peptidase-1) is a lysosomal enzyme delivered via ICV infusion directly to the brain to replace the deficient enzyme. This therapy is the first safe and effective ICV ERT approved for direct delivery to the brain. A Phase II clinical trial is also underway using a modified lysosomal enzyme ICV-delivered directly to the brain. Together, the FDA and investors are familiar with ERT and its commercialization path forward, both of which are essential in reaching a clinical trial. This proposal focuses on the development of the ICV route of administration to perform ERT directly to the central nervous system and its application to treating GM1 gangliosidosis. GM1 gangliosidosis has severe neurodegenerative symptoms with no current therapies available due to poor transport across the blood-brain barrier. In our studies, we will engineer cells to produce sufficient quantities of recombinant human beta-galactosidase enzyme for testing in GM1 gangliosidosis knockout mice. These mice will be ICV-administered enzyme and analyzed for dose-dependent biodistribution of the enzyme and effects on biochemical and histological pathology will be evaluated. Efficacy and safety will be assessed in single intermittent dose; once a week for 8 weeks dosing study. The results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans.
Public Health Relevance Statement: PROJECT NARRATIVE The goal of this proposal is to develop a novel method of enzyme delivery to the brain. Intravenous enzyme replacement therapy has proven successful for treating the somatic symptoms of lysosomal storage disorders, but delivery to the central nervous system is problematic because intravenously injected enzymes do not penetrate the blood brain barrier. In this proposal, we test an intrathecal delivery; known as intracerebroventricular, which provides direct injection to the brain and therefore bypasses the blood brain barrier, as a therapy for treating patients with GM1 gangliosidosis. GM1 gangliosidosis is a lethal childhood disease that is currently without any treatments. Previous clinical trials as well as ongoing clinical trials with lysosomal enzymes as drugs for treating other lysosomal diseases suggest that an intracerebroventricular delivery approach has a very high probability of success.
Project Terms: L-Iduronate-2-sulfate 2-sulfohydrolase; Sulfoiduronate Sulfatase; L-Iduronidase; Glycosaminoglycan alpha-L-iduronohydrolase; Glycosaminoglycan a-L-iduronohydrolase; Iduronidase; alpha-L-Idosiduronase; alpha-L-Iduronidase; a-L-Idosiduronase; a-L-Iduronidase; 21+ years old; Adult Human; adulthood; Adult; beta-Galactosidase; beta-D-Galactosidase; beta-D-Galactoside galactohydrolase; lac Z Protein; ß-D-Galactosidase; ß-D-Galactoside galactohydrolase; ß-Galactosidase; Biological Assay; Assay; Bioassay; Biologic Assays; Blood - brain barrier anatomy; Blood-Brain Barrier; Hemato-Encephalic Barrier; bloodbrain barrier; Western Blotting; Immunoblotting; Western Immunoblotting; protein blotting; bone; Bone Marrow; Bone Marrow Reticuloendothelial System; Brain; Brain Nervous System; Encephalon; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; Cerebral Ventricles; Brain Ventricle; Child; 0-11 years old; Child Youth; Children (0-21); kids; youngster; Clinical Trials; Cessation of life; Death; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Enzyme Tests; Enzymes; Enzyme Gene; Exhibits; Fibroblasts; Ganglioside GM1; G(A(2)) Ganglioside; G(M1) Ganglioside; GA(2) Ganglioside; Monosialosyl Tetraglycosyl Ceramide; Galactose; D-Galactose; Galactopyranose; Galactopyranoside; Gangliosides; Sialoglycosphingolipids; Gene Amplification; natural gene amplification; Beta-glucuronidase; Glucuronidase; beta-D-Glucuronoside glucuronosohydrolase; ß-D-Glucuronoside glucuronosohydrolase; ß-glucuronidase; Goals; Heart; Hip region structure; Coxa; Hip; Human; Modern Man; Hydrolase; Hydrolase Family Gene; Hydrolase Gene; iduronate-2-sulfatase; Hunter Corrective Factor; Iduronate Sulfatase; Iduronate Sulfate Sulfatase; Iduronatesulfate Sulfohydrolase; In Vitro; Intravenous infusion procedures; IV Infusion; intravenous infusion; Mucopolysaccharidosis I; MPS 1; MPS I; Mucopolysaccharidosis 1; alpha-L-iduronidase (IDA, IDUA) deficiency; alpha-L-iduronidase deficiency; iduronidase deficiency disease; mucopolysaccharide storage disease I; mucopolysaccharidosis (MPS) I; mucopolysaccharidosis type I; a-L-iduronidase (IDA, IDUA) deficiency; Literature; Liver; hepatic body system; hepatic organ system; Lysosomes; Marketing; Methods; Methotrexate; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Morbidity - disease rate; Morbidity; Motor Skills; Mucopolysaccharidoses; Mucopolysaccharidosis; Mucopolysaccharidosis II; Hunter Syndrome Gargoylism; Hunter syndrome; Hunter-Fraser syndrome; MPS II; Mucopolysaccharidosis 2; X-linked Hurler syndrome; iduronate sulfatase deficiency; iduronate-2-sulfatase deficiency; mucopolysaccharide storage disease II; mucopolysaccharidosis type II; sulfo-iduronate sulfatase deficiency; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Nerve Degeneration; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Pathology; Patients; Polysaccharides; Glycans; Probability; Production; Quality of life; QOL; Research; Safety; Scalp structure; Scalp; scoliosis; Seizures; Testing; Dihydrofolate Reductase; Dihydrofolate Dehydrogenase; Folic Acid Reductase; Tetrahydrofolate Dehydrogenase; Tissues; Body Tissues; Measures; Lysosomal Enzyme Disorders; inborn lysosomal enzyme disorder; lysosomal disease; lysosomal disorder; lysosome storage diseases; Lysosomal Storage Diseases; CHO Cells; Chinese Hamster Ovary Cell; Caffey pseudo-Hurler syndrome; Caffey syndrome; G(M1) Gangliosidosis; Hurler variant; Hurler-like syndrome; Landing syndrome; Norman-Landing syndrome; Tay-Sachs disease with visceral involvement; beta galactosidase deficiency; beta-galactosidase-1 (GLB1) deficiency; beta-galactosidase-1 deficiency; cerebral GM1 gangliosidosis; familial neurovisceral lipidosis; generalized infantile gangliosidosis; generalized infantile gangliosidosis with bony involvement; neuronal Gm(1) gangliosidosis; neurovisceral lipidosis; pseudo-Hurler disease; type I gagliosidosis GM1; type I generalized gangliosidosis GM1; Gangliosidosis GM1; GUSB deficiency; MPS VII; MPSVII; Mucopolysaccharidosis 7; Sly Disease; Sly Syndrome; beta-glucuronidase deficiency; beta-glucuronidase deficiency mucopolysaccharidosis; mucopolysaccharide storage disease VII; mucopolysaccharidosis (MPS) VII; mucopolysaccharidosis type VII; ß-glucuronidase deficiency; Mucopolysaccharidosis VII; Catheters; Developmental Delay; Specific Child Development Disorders; Developmental Delay Disorders; Ellis-Sheldon syndrome; Hurler Syndrome Gargoylism; Hurler syndrome; Hurler's Disease; Hurler's Syndrome; Johnie McL syndrome; Lipochondrodystrophy; MPS I H; chondro-osteodystrophy-corneal; dysostotic idiocy-gargoylism-lipochondrodystrophy syndrome; gargoylism; opacities-hepatosplenomegaly mental deficiency syndrome; Mucopolysaccharidosis I H; enzyme deficiency; Chronic; prematurity; premature; Penetration; Residual; Residual state; Histologically; Histologic; Biochemical; Adolescent Youth; juvenile; juvenile human; Adolescent; KO mice; Knock-out Mice; Null Mouse; Knockout Mice; Link; infantile; infancy; pediatric; Childhood; Neurologic Manifestations; Neurologic Signs and Symptoms; Neurological Manifestations; Neurological Signs and Symptoms; neural manifestation; Neurologic Symptoms; Bilateral; sugar; Disease Progression; enzyme activity; uptake; central nervous system degeneration; CNS degeneration; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Phase 2 Clinical Trials; phase II protocol; Phase II Clinical Trials; Therapeutic; Dysplasia; dyscrasia; Intravenous; Life; Complex; Route; restoration; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Infusion procedures; Infusion; infusions; autosome; mutant; success; enzyme replacement therapy; Protein Replacement Therapy; Animal Model; Animal Models and Related Studies; model of animal; clinical trials in animals; recessive genetic trait; genetic recessive; recessive trait; novel; Reporting; Bypass; Spielmeyer-Vogt Disease; Batten Disease; Batten-Mayou Disease; Batten-Spielmeyer-Vogt Disease; therapeutic enzyme; neuropathology; neuropathologic; neuropathological; Central Nervous System; CNS Nervous System; Neuraxis; Ommaya Reservoir; preventing; prevent; tripeptidyl aminopeptidase; tripeptidyl peptidase; Dose; Symptoms; Bolus Infusion; Bolus; Recombinants; Therapy Clinical Trials; Validation; validations; Preparation; preparations; Process; Development; developmental; pre-clinical; preclinical; preclinical study; pre-clinical study; clinical phenotype; IQ Deficit; intelligence quotient deficit; neurocognitive decline; neurocognitive impairment; Neurocognitive Deficit; Biodistribution; 5 years of age; age 5 years; five year old; five years of age; 5 year old; Implant; progressive neurodegeneration; commercialization; effective treatment; effective therapy; in vitro activity; behavior study; behavioral study; GLB1; GLB1 gene; Injections; genetic condition; genetic disorder; Genetic Diseases; BBB crossing; bloodbrain barrier crossing; blood-brain barrier crossing; Circulation
