The current inability to effectively deliver corrective doses of lysosomal enzymes to key cells involved in cardiovascular and cerebrovascular disease remains a significant hurdle for rare lysosomal disorders (LSD) such as Fabry disease and other diseases with significant cardiovascular pathologies. BioStrategies LC is developing the plant lectin RTB as a carrier capable of expanding enzyme delivery to hard-to-treat organs and tissues including heart, brain, and bone. Lectin mediated ERT delivery has recently shown promise in other LSDs including MPS I and GM1. This SBIR is focused on developing a delivery-enhanced enzyme replacement therapy (ERT) for patients with Fabry disease. Fabry is a X-linked LSD caused by genetic deficiencies in alpha- galactosidase A (?-GalA) leading to severe multi-organ pathologies with cardiac death, followed by stroke, as the leading causes of death. Fabry disease has emerged as the key LSD model for heart disease due to extensive cardiomyopathy and other cardiovascular presentations. Our long-term goal is to bring an ERT capable of treating the full spectrum of progressive cardiac and other disease manifestations to Fabry patients. Objectives of this Phase I SBIR feasibility study are to produce bioactive ?- GalA:RTB fusions and demonstrate product delivery into human myocytes, correction of lysosomal phenotype in Fabry cells, and biodistribution to heart and other tissues in the Fabry mouse model. Success in Phase I feasibility goals will support moving on to rigorous Phase II SBIR follow-up preclinical assessments aimed at moving this promising ERT product to an IND. The feasibility established here will also support expanding the RTB carrier system to other ERTs and therapeutics for diseases having life-threatening cardiovascular involvement.
Public Health Relevance Statement: NARRATIVE
Public Health Relevance: The family of human genetic diseases represented by Fabry Syndrome and other rare lysosomal disorders include some of the most devastating human afflictions known and the most costly to patients, their families, and the public health system. This project addresses the need for delivering enzyme replacement therapeutics (ERT) drugs to cardiac tissues, a problem that currently available ERT drugs for this disease do not address and Fabry disease is particularly appropriate for this project because carriers of this genetic defect often suffer from Fabry related cardiac problems as the leading cause of death. The innovative RTB-ERT drug delivery technology developed in this project would further the US national goal of reducing heart disease in general and the suffering and costs for patients afflicted more specifically with Fabry and other genetic and metabolic diseases which affect normal cardiac development.
NIH Spending Category: Biotechnology; Cardiovascular; Heart Disease; Mucopolysaccharidoses (MPS); Neurodegenerative; Orphan Drug; Pediatric; Rare Diseases
Project Terms: Address; Affect; Affinity; Alpha-galactosidase; Animals; Antibodies; base; Behavior; Biodistribution; bone; Brain; Cardiac; Cardiac Death; Cardiac development; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cause of Death; cell type; Cells; Cerebrovascular Disorders; Chimeric Proteins; Codon Nucleotides; cost; Data; Detection; Disease; Disease model; Dose; Drug Delivery Systems; enzyme activity; Enzyme Kinetics; enzyme replacement therapy; Enzymes; Exhibits; Fabry Disease; Family; Feasibility Studies; Fibroblasts; fluorescence imaging; follow-up; fusion gene; Gangliosidosis GM1; Genetic; Genetic Carriers; Genetic Diseases; globotriaosylceramide; Goals; Health system; Heart; Heart Diseases; Human; Human Genetics; Immune; Immunohistochemistry; In Vitro; in vivo; Injections; innovation; Kidney; Kinetics; L-Iduronidase; Lead; Learning; Lectin; Life; Link; Liver; Longitudinal Studies; Lysosomal Storage Diseases; Lysosomes; Mammalian Cell; Mediating; Memory; Metabolic Diseases; mouse model; Mucopolysaccharidosis I; Mus; Muscle Cells; Mutation; Nicotiana; Organ; Other Genetics; Pathology; Patients; Pharmaceutical Preparations; Phase; phase 2 study; Phenotype; Plant Lectins; pre-clinical; Production; Progressive Disease; Proteins; Public Health; public health relevance; Small Business Innovation Research Grant; Spleen; Stroke; success; Syndrome; System; Technology; Testing; Therapeutic; therapeutic effectiveness; Tissues; uptake
