Morquio A therapy integrating gene transfer with lectin-enhanced enzyme delivery to treat multisystemic clinical impairments of rare metabolic childhood diseases

Morquio 一种将基因转移与凝集素增强酶递送相结合的疗法，用于治疗罕见代谢性儿童疾病的多系统临床损伤

• 批准号: 10821924
• 负责人: Walter Acosta
• 金额: $ 29.59万
• 依托单位: BIOSTRATEGIES, LC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10821924
• 关键词: Acetylgalactosamine; Address; Affect; Antibodies; Behavioral; Benchmarking; Binding; Biodistribution; Biological Models; Cardiac; Cardiovascular system; Caregivers; Cartilage; Cells; Central Nervous System; Cessation of life; Child; Childhood; Chondrocytes; Chondroitin Sulfates; Clinic; Clinical; Connective Tissue; Data; Deposition; Development; Disease; Dose; Effectiveness; Enzymes; Epiphysial cartilage; Exhibits; Family; Galactosamine; Galactose; Gene Transfer; Genes; Genetic; Genetic Diseases; Goals; Half-Life; Health system; Heart; Heart Valves; Human; Human Genetics; Immune; Immune Sera; Immune response; Impairment; Infusion procedures; Keratan Sulfate; Kidney; Lead; Lectin; Length; Ligaments; Liver; Lung; Lysosomal Storage Diseases; Lysosomes; Mammalian Cell; Mediating; Medical; Metabolic; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis IV A; Mus; Musculoskeletal; Organ; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phase; Plant Lectins; Progressive Disease; Protein Secretion; Public Health; Quality of life; Recombinants; Research; Respiration Disorders; Serum; Site; Skeletal Muscle; Small Business Innovation Research Grant; Specificity; Sulfatases; Sulfate; Technology; Testing; Therapeutic Effect; Time; Tissues; Toxicology; Trachea; Transfection; Translating; bone; cost; design; drug efficacy; enzyme activity; enzyme replacement therapy; gene therapy; glucosaminoglycans; immunogenicity; improved; in vitro testing; ineffective therapies; lead candidate; manufacture; mouse model; pre-clinical; preclinical study; promoter; public health relevance; rare genetic disorder; respiratory; skeletal; transgene expression; treatment strategy; uptake

Mucopolysaccharidosis Type IVA (MPS-IVA; also called Morquio A Syndrome) is a rare genetic childhood disorder characterized by multi-systemic pathologies affecting the respiratory, cardiovascular, musculoskeletal, and central nervous systems leading to devastating quality-of-life and early death. The disease is due to deficiencies in N-acetylgalactosamine-6-sulfate sulfatase (GALNS) causing progressive and pathological accumulation of the glucosaminoglycans (GAGs) keratan sulfate and chondroitin sulfate in multiple organs and tissues. The impact of keratan/chondroitin sulfate accumulation on bone, cartilage, and connective tissues is particularly striking, leading to debilitating cardiac, respiratory, and skeletal pathologies. An enzyme replacement therapy (ERT) comprising recombinant human GALNS is currently available but shows no improvement of these pathologies. Immunogenicity involving the development of neutralizing anti-drug antibodies is also an issue with this ERT. BioStrategies LC has developed an enzyme delivery technology based on the plant lectin RTB which greatly enhances delivery of fused enzymes to hard-to-treat cells and tissues including musculoskeletal, cardiac, respiratory and central nervous systems – sites that have been particularly recalcitrant to effective delivery of corrective doses of replacement enzymes. Previous studies using murine MPS I as a model system demonstrated that weekly treatment with enzyme-RTB fusions showed normalization of key bone structural parameters, CNS substrate accumulation, and behavioral benchmarks of the disease. Additionally, the RTB carrier successfully mitigated any issues associated with anti-drug immunogenicity. Thus, RTB-mediated delivery may address the key limitation of current Morquio ERTs to treat the debilitating multisystemic pathologies of this disease. Our goal in this SBIR is to develop a ”delivery-enhanced” gene therapy drug comprising an RTB:GALNS fusion and to perform key preclinical studies. The specific aims of this Phase I SBIR are to 1) Develop and optimize an RTB:GALNS construct for optimal expression and secretion that retain enzymatic activity and lectin binding capacity; 2) Determine long-term transgene expression and serum stability by assessing different promoters; and 3) Evaluate biodistribution of the enzyme and substrate reduction in difficult-to-treat tissues in the Morquio A mouse model. Our objective is to translate these breakthroughs to produce a “delivery-enhanced” MPS IVA therapy that will effectively treat disease manifestations that remain a significant unmet medical need for these patients. The proof of concept generated in these studies will provide the basis to design IND enabling studies in a Phase II that include GMP manufacture plans, tox studies, and regulatory IND submissions.

粘多糖病IVA型（MPS-IVA，也称为Morquio A综合征）是一种罕见的遗传性儿童期疾病