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 型粘多糖贮积症（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破坏性的生活质量和过早死亡。 N-乙酰半乳糖胺-6-硫酸酯硫酸酯酶 (GALNS) 缺陷导致进行性和病理性 葡萄糖胺聚糖 (GAG) 硫酸角质素和硫酸软骨素在多个器官中积累， 角质素/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，导致心脏、呼吸系统和骨骼疾病的衰弱。 目前可以使用包含重组人 GALNS 的疗法（ERT），但没有显示出这些方面的改善 涉及中和抗药物抗体的产生的免疫原性也是一个问题。 BioStrategies LC 开发了一种基于植物凝集素 RTB 的酶输送技术。 极大地增强了融合酶向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——特别难以有效输送物质的部位 先前的研究使用小鼠 MPS I 作为模型系统。 每周用酶-RTB 融合进行治疗表明关键骨结构正常化 参数、中枢神经系统底物积累和疾病的行为基准，以及 RTB。 载体成功地缓解了与抗药物免疫原性相关的任何问题。 递送可能会解决当前 Morquio ERT 治疗衰弱性多系统疾病的关键局限性 这种疾病的病理。 我们在本次 SBIR 中的目标是开发一种包含 RTB:GALNS 的“递送增强”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 构建体以实现最佳表达和分泌，同时保留酶活性和凝集素 2) 通过评估不同的结合能力来确定长期转基因表达和血清稳定性 3) 评估难以治疗的组织中酶的生物分布和底物减少 Morquio A 小鼠模型的目标是将这些突破转化为“交付增强”。 MPS IVA 疗法将治疗仍未有效满足医疗需求的疾病表现 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。