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(MPS-IVA；又称Morquio A综合征)是一种罕见的儿童遗传性疾病 疾病的特征是影响呼吸、心血管、肌肉骨骼、 和中枢神经系统导致毁灭性的生活质量和过早死亡。这种疾病是由于 N-乙酰半乳糖胺-6-硫酸酯酶(GALNS)缺陷导致进展性和病理性 氨基葡聚糖(GAG)、硫酸角蛋白和硫酸软骨素在多个器官和组织中的积累 纸巾。角蛋白/硫酸软骨素的堆积对骨、软骨和结缔组织的影响是 尤其令人震惊，导致心脏、呼吸和骨骼病理衰弱。一种酶替代物 包含重组人GALN的治疗(ERT)目前是可用的，但没有显示出改善 病理学。免疫原性涉及中和抗药物抗体的发展也是一个问题 这是急诊室。BioStrategy LC开发了一种基于植物凝集素RTB的酶传递技术，该技术 极大地增强了融合酶对难以治疗的细胞和组织的输送，包括肌肉骨骼、心脏、 呼吸系统和中枢神经系统--那些特别顽固地不能有效地提供 正确剂量的替代酶。以往以小鼠MPS I为模型系统的研究 证实每周一次的酶-rtb融合治疗显示关键骨结构正常化。 参数、中枢神经系统底物蓄积和疾病的行为基准。此外，RTB 承运人成功缓解了与抗药免疫原性相关的任何问题。因此，RTB中介的 交付可能解决目前Morquio ERT治疗衰弱的多系统疾病的关键限制 这种疾病的病理学。 我们在这项SBIR中的目标是开发一种“递送增强型”基因治疗药物，包括rtb：GALNS 并进行关键的临床前研究。此第一阶段SBIR的具体目标是：1)开发和 优化RTB：GALNS结构以获得保持酶活性和凝集素的最佳表达和分泌 结合能力；2)通过评估不同的基因表达和血清稳定性来确定转基因的长期表达 以及3)评估该酶在难治疗组织中的生物分布和底物还原。 Morquio A小鼠模型。我们的目标是将这些突破转化为“增强交付” MPS IVA疗法将有效地治疗仍然是一个重要的未得到满足的医疗需求的疾病表现 对这些病人来说。在这些研究中产生的概念证明将为设计IND使能提供基础 第二阶段的研究，包括GMP生产计划、毒性研究和法规IND提交。