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

基本信息

  • 批准号:
    10821924
  • 负责人:
  • 金额:
    $ 29.59万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

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Walter Acosta其他文献

Walter Acosta的其他文献

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{{ truncateString('Walter Acosta', 18)}}的其他基金

Krabbe disease therapy integrating gene transfer with lectin-enhanced enzyme delivery to treat pathologies of the CNS
克拉伯病疗法将基因转移与凝集素增强酶递送相结合,以治疗中枢神经系统疾病
  • 批准号:
    10547167
  • 财政年份:
    2022
  • 资助金额:
    $ 29.59万
  • 项目类别:
Improving MPS I ERT Efficacy through Lectin-Mediated Delivery
通过凝集素介导的递送提高 MPS I ERT 功效
  • 批准号:
    9346992
  • 财政年份:
    2017
  • 资助金额:
    $ 29.59万
  • 项目类别:
Enzyme Replacement Therapeutics for Rare Childhood Genetic Diseases: An ERT Delivery System that Mitigates Immune-sensitization
罕见儿童遗传病的酶替代疗法:减轻免疫敏化的 ERT 递送系统
  • 批准号:
    9048190
  • 财政年份:
    2016
  • 资助金额:
    $ 29.59万
  • 项目类别:

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