BioStrategies LC is developing the plant galactose-binding lectin, RTB, as an enzyme carrier capable of expanding delivery of enzyme replacement therapies (ERTs) to "hard- to-treat" organs and tissues such as bone. The rare lysosomal disease mucopolysaccharidosis I (MPS I) is a progressive multisystem disorder, which presents with significant skeletal abnormalities that play a major role in patient disease progression. MPS I is caused by genetic deficiencies in the lysosomal enzyme a-L- iduronidase (IDUA) which is critical for glycosaminoglycan degradation. Pathological accumulation of dermatan sulfate is particularly problematic in the musculoskeletal system leading to dysostosis, course facial features, short stature, arthropathy, and joint stiffness. Early-onset forms (Hurler syndrome) are typically treated by bone marrow transplantation and/or currently available ERT. However these treatments, alone or in combination, do not adequately correct or arrest skeletal disease progression. Preliminary studies indicate that our RTB-IDUA drug (IDUAL) may deliver the iduronidase lysosomal enzyme to bones of MPS I mouse model animals. The goal of this proposal is to demonstrate the feasibility of IDUAL to effectively treat the bone and connective tissues in the MPS I mouse. Specific Aims of this proposal are to 1) Assess the impacts of IDUAL treatment on early pathogenic events in MPS I animals during the bone growth phase, and 2) Evaluate molecular and morphometric readouts of MPS I skeletal pathologies during the bone remodeling phase following long-term treatment with IDUAL. Based on these proof-of-concept results, Phase II studies would support the scale-up manufacturing and rigorous preclinical assessments to move this promising product to an IND approval. The feasibility established here will also support extending the RTB carrier system to ERTs for other diseases having debilitating musculoskeletal involvement.
Public Health Relevance Statement: NARRATIVE -
Public Health Relevance: The family of human genetic diseases represented by MPS I and other rare lysosomal disorders (LDs) include some of the most devastating human afflictions known and the most costly to patients, their families, and the public health system. The currently approved enzyme replacement therapeutics (ERTs) available to treat several of these diseases, although effective for many patients, still suffer from problems of safety, high cost, availability of adequate product supplies to patient populations, and product effectiveness in treating all organs of body. The new therapeutics technologies for MPS I developed in this SBIR Phase I R&D project would address all of these issues by employing new drug delivery technology that more effectively targets affected cell types, cellular compartments, and organs. The need for delivering these new treatment options for treating the skeletal system is particularly critical as current drug options for LDs are generally not effective in bone development disease. The innovative drug delivery technology developed in this project including our use of cheaper plant-based manufacturing would further the national goal of reducing the suffering and costs for patients afflicted with MPS I and others of these devastating genetic diseases.
Project Terms: Affect; Age; ages; Animals; Architecture; Engineering / Architecture; bone; Bone Density; Bone Mineral Density; Bone Development; Bone Marrow Transplantation; Marrow Transplantation; Bone Marrow Transplant; Bone Marrow Grafting; Brain; Encephalon; Brain Nervous System; Connective Tissue; Connective Tissue Diseases; Connective Tissue Disorder; Dermatan Sulfate; beta-Heparin; Chondroitin Sulfate B; Disease; Disorder; Pharmacotherapy; drug treatment; Drug Therapy; Pharmaceutical Preparations; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Enzymes; Enzyme Gene; Exhibits; Extracellular Matrix; ECM; Cell-Extracellular Matrix; Face; facial; faces; Family; Feasibility Studies; Fibroblasts; Gene Expression; Glycolipids; Glycoproteins; Glycosaminoglycans; Mucopolysaccharides; Goals; Heart; Human; Modern Man; Human Genetics; L-Iduronidase; a-L-Iduronidase; a-L-Idosiduronase; alpha-L-Iduronidase; alpha-L-Idosiduronase; Iduronidase; Glycosaminoglycan a-L-iduronohydrolase; Glycosaminoglycan alpha-L-iduronohydrolase; arthropathies; joint disorder; arthropathy; arthropathic; Joint Diseases; Joints; Kidney; renal; Kidney Urinary System; Kinetics; Learning; Lectin; Mucopolysaccharidosis I; a-L-iduronidase (IDA, IDUA) deficiency; mucopolysaccharidosis type I; mucopolysaccharidosis (MPS) I; mucopolysaccharide storage disease I; iduronidase deficiency disease; alpha-L-iduronidase deficiency; alpha-L-iduronidase (IDA, IDUA) deficiency; Mucopolysaccharidosis 1; MPS I; MPS 1; Liver; hepatic organ system; hepatic body system; Memory; Mucopolysaccharidoses; Mucopolysaccharidosis; Mus; Murine; Mice Mammals; Mice; Musculoskeletal System; locomotor system; Pathology; Patients; Plants; Play; Public Health; Quality of life; QOL; research and development; R&D; R & D; Development and Research; Ricin; Ricinus Toxin; Ricinus Lectin; Ricinus Communis Agglutinin II; RCA60; RCA 60; Castor Bean Lectin; Role; social role; Safety; Siblings; Signal Transduction; biological signal transduction; Signaling; Signal Transduction Systems; Intracellular Communication and Signaling; Cell Signaling; Cell Communication and Signaling; Skeletal system; Specificity; Spleen; Spleen Reticuloendothelial System; Technology; Testing; Tissues; Body Tissues; Urine; Urine Urinary System; Drug Delivery Systems; Drug Delivery; Mucopolysaccharidosis VII; ß-glucuronidase deficiency; mucopolysaccharidosis type VII; mucopolysaccharidosis (MPS) VII; mucopolysaccharide storage disease VII; beta-glucuronidase deficiency mucopolysaccharidosis; beta-glucuronidase deficiency; Sly Syndrome; Sly Disease; Mucopolysaccharidosis 7; MPSVII; MPS VII; GUSB deficiency; Bone remodeling; bone remodelling; Mucopolysaccharidosis I H; opacities-hepatosplenomegaly mental deficiency syndrome; gargoylism; dysostotic idiocy-gargoylism-lipochondrodystrophy syndrome; chondro-osteodystrophy-corneal; MPS I H; Lipochondrodystrophy; Johnie McL syndrome; Hurler's Syndrome; Hurler's Disease; Hurler syndrome; Hurler Syndrome Gargoylism; Ellis-Sheldon syndrome; IGF Type 2 Receptor; Mannose-6-Phosphate Receptor; Insulin-Like Growth Factor Type 2 Receptor; Insulin-Like Growth Factor II Receptor; IGF-II Receptor; IGF-2 Receptor; joint stiffness; Fusion Protein; Chimera Protein; Chimeric Proteins; base; Organ; Phase; Measurement; Disease Progression; enzyme activity; uptake; skeletal disease; skeletal disorder; Therapeutic; Plant Lectins; Genetic; Morphology; Intravenous; Bone Tissue; Event; Visceral; cell type; System; Musculoskeletal; skeletal; Spinal; skeletal tissue; transcytosis; enzyme replacement therapy; Protein Replacement Therapy; Animal Model; model organism; model of animal; Animal Models and Related Studies; Galactose Binding Lectin; beta-Galactoside Binding Lectin; beta-D-Galactosyl-Specific Lectin; S-Type Lectins; Galectins; Galaptins; D-Galactoside-Binding Lectin; Rare Diseases; orphan disorder; Rare Disorder; Orphan Disease; novel; Cell surface; Skeleton; Bone Growth; Pathogenicity; Binding; Molecular Interaction; Effectiveness; Progressive Disease; Address; Dose; Health system; Affinity; Data; Glycosaminoglycan Degradation Pathway; Glycosaminoglycan Degradation; Mammalian Cell; Recombinants; in vivo; Small Business Innovation Research; SBIR; Small Business Innovation Research Grant; Pathologic; Characteristics; Molecular; developmental; Development; imaging; Image; preclinical; pre-clinical; early onset; National Institute of Neurological Diseases and Stroke; NINDS; National Institute of Neurological Disorders and Stroke; disease phenotype; cost; innovative; innovate; innovation; novel therapy; novel drugs; novel drug treatments; next generation therapeutics; new therapy; new therapeutics; new drugs; new drug treatments; novel therapeutics; murine model; mouse model; public health relevance; patient population; biomarker; biologic marker; bio-markers; Biological Markers; manufacturing scale-up; skeletal abnormality; phase II study; phase 2 study; genetic disorder; genetic condition; Genetic Diseases
