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.

IVA型粘多糖样变性（MPS-IVA;也称为Morquio A综合征）是一种罕见的遗传性儿童病 以影响呼吸、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-硫酸酯硫酸酯酶（GALNS）缺乏导致进行性和病理性 葡糖胺聚糖（GAG）、硫酸角质素和硫酸软骨素在多个器官中蓄积， 组织中角蛋白/硫酸软骨素积累对骨、软骨和结缔组织的影响是 特别引人注目的是，导致使人衰弱的心脏、呼吸系统和骨骼病变。酶替代 包含重组人GALNS的ERT治疗（ERT）目前是可获得的，但没有显示出这些改善。 病理学涉及中和抗药抗体的发展的免疫原性也是免疫治疗的一个问题。 这个ERT。BioStrategies LC开发了一种基于植物凝集素RTB的酶递送技术， 极大地增强了融合酶向难以治疗的细胞和组织的递送，包括肌肉骨骼，心脏， 呼吸系统和中枢神经系统----特别难以有效提供 补充酶的正确剂量先前使用鼠MPS I作为模型系统的研究 结果表明，每周一次的酶-RTB融合治疗显示关键骨结构正常化， 参数、CNS底物积累和疾病的行为基准。此外，RTB 载体成功地减轻了与抗药物免疫原性相关的任何问题。因此，RTB介导 递送可以解决当前Morquio Erts治疗衰弱的多系统性 这种疾病的病理。 我们在该SBIR中的目标是开发包含RTB：GALNS的“递送增强的”基因治疗药物。 融合并进行关键的临床前研究。第一阶段SBIR的具体目标是：1）开发和 优化RTB：GALNS构建体以获得最佳表达和分泌，其保留酶活性和凝集素 2）通过评估不同的转基因结合能力来确定长期转基因表达和血清稳定性; 启动子;和3）评估酶的生物分布和底物在难处理组织中的减少， Morquio A小鼠模型。我们的目标是将这些突破转化为“交付增强型” MPS IVA治疗将有效治疗仍然是一个显著未满足的医疗需求的疾病表现 对于这些患者。这些研究中产生的概念验证将为设计IND提供基础， II期研究，包括GMP生产计划、毒性研究和监管IND提交。