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型粘二糖（MPS-IVA；也称为Morquio A综合征）是罕见的遗传儿童时期 疾病以多种系统病理的特征，影响呼吸道，心血管，肌肉骨骼， 中枢神经系统导致毁灭性的生活质量和早期死亡。该疾病是由于 N-乙酰乳糖胺-6-硫酸硫酸盐硫酸盐酶（GALNS）的缺陷，导致进行性和病理学 葡糖胺聚糖（GAGS）硫酸葡萄糖糖聚糖和硫酸软骨素在多个器官中的积累 组织。瑞士/软骨素硫酸盐积累对骨骼，软骨和连接组织的影响是 特别引人注目，导致心脏，呼吸和骨骼病理使人衰弱。酶的替代 目前可获得完成重组人奶油的治疗（ERT），但没有任何改善 病理。免疫原性涉及中和中和抗药物抗体的发展也是 这个ert。 BioStrategies LC已根据植物讲座RTB开发了一种酶输送技术 大大增强了融合酶的递送到难以治疗的细胞和组织，包括肌肉骨骼，心脏， 呼吸道和中枢神经系统 - 特别是在有效交付的地方 矫正剂量的替代酶。以前使用鼠MPS I作为模型系统的研究 证明每周用酶-RTB融合的治疗显示了关键骨结构的归一化 参数，CNS底物积累和疾病的行为基准。另外，RTB 携带者成功地减轻了与抗药物免疫原性相关的任何问题。那是RTB介导的 交付可以解决当前Morquio ERT的关键限制，以治疗衰弱的多系统 这种疾病的病理。 我们在这个SBIR中的目标是开发一种“递送增强”基因治疗药物完成RTB：GALNS 融合并进行关键的临床前研究。该阶段I SBIR的具体目的是1）开发和 优化RTB：galns构造，以保持最佳表达和分泌，以保留酶活性和教堂 结合能力； 2）通过评估不同的方式确定长期转化表达和血清稳定性 发起人； 3）评估酶的生物分布和减少难以治疗时机的底物的生物分布 Morquio鼠标模型。我们的目标是翻译这些突破，以产生“交付增强” MPS IVA疗法将有效地治疗疾病表现，这仍然是巨大的未满足医疗需求 对于这些患者。这些研究中产生的概念证明将为设计IND启用提供基础 在包括GMP制造计划，TOX研究和法规提交的II期研究中的研究。