MPS I (Hurler Syndrome) is a disease in which a key enzyme is missing in cells resulting in the accumulation of a type of complex sugar called a glycosaminoglycan, in various tissues. A primary approach for treating related types of disorders involves replacement of the missing enzyme by injection into the circulation. Enzyme replacement therapy resolves many aspects of the disease but unfortunately it does not resolve complications of the disease in the central nervous system. This proposal focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS I, a disease with good systemic effects, but no effect on the neurodegenerative process symptoms due to poor transport across the blood-brain barrier. Using iduronidase (IDUA) conjugated to guanidinoneomycin (GNeo), a molecular transporter, we showed that we can deliver the missing enzyme to cells derived from MPS I patients and that intravenous injection of modified enzyme reduces storage of glycosaminoglycans in a mouse model of MPS I (IDUA-/-). Furthermore, intranasal administration of GNeo-IDUA demonstrated that small amounts of enzyme were delivered to the brain and were able to reduce pathological glycosaminoglycans. The purpose of this grant is to assess the effectiveness of enzyme replacement therapy delivered directly to the central nervous system in the MPS I mouse model using intracerebroventricular administration. Dose-dependent biodistribution of GNeo-IDUA and the effect on biochemical and histological pathology and behavior will be evaluated. Efficacy and safety will be assessed in single dose and 2-week dosing studies. The results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans.
Project Terms: Abbreviations; acute toxicity; Animals; base; Behavior; behavioral study; Biochemical; Biodistribution; Biological Markers; Blood - brain barrier anatomy; Blood Circulation; Brain; Bypass; Carbohydrates; Cell membrane; Cell surface; Cells; Cerebrospinal Fluid; Chondroitin; CNS degeneration; Complex; Cultured Cells; Deposition; Dermatan Sulfate; Development; Disease; Dose; drug development; Drug Kinetics; Effectiveness; Endocytosis; enzyme replacement therapy; Enzymes; Excretory function; Feasibility Studies; GAG Gene; Glycosaminoglycan Degradation Pathway; Glycosaminoglycans; Glycosides; Glycosphingolipids; Goals; Grant; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hepatic; Histologic; Human; Hyaluronan; Iduronic Acid; IGF Type 2 Receptor; in vivo; Inflammation; Injections; Intranasal Administration; Intravenous; intravenous injection; L-Iduronidase; Lysosomes; mannose 6 phosphate; Measures; Mental Retardation; Methods; Modeling; molecular transporter; Molecular Weight; mouse model; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mus; Mutation; Neomycin; Nerve Degeneration; Neuraxis; Neurologic Symptoms; novel; Pathologic; Pathology; Patients; Penetration; Pharmaceutical Preparations; Phase; pre-clinical; prevent; Process; Program Development; Proteins; Recombinants; Safety; Spinal Cord; Structural Genes; sugar; Symptoms; System; Testing; Time; Tissues; Toxic effect; Urine;
