将记忆 T 细胞工程作为溶酶体贮积症长期酶替代疗法的平台。

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-10-04 DOI:10.1016/j.ymthe.2024.09.033
Evan W Kleinboehl, Kanut Laoharawee, Jacob D Jensen, Joseph J Peterson, Nicholas J Slipek, Bryce J Wick, Matthew J Johnson, Beau R Webber, Branden S Moriarity
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引用次数: 0

摘要

酶病是酶缺失或缺陷的结果。在这些酶病中,I 型粘多糖病是一种罕见的遗传性溶酶体贮积症,由编码 alpha-L-iduronidase (IDUA) 的基因突变引起,最终导致糖胺聚糖 (GAG) 的毒性积聚。目前尚无根治方法,标准疗法也不能充分缓解骨骼结构和中枢神经系统(CNS)的症状。人类记忆 T 细胞(Tm)可在全身组织中迁移,并可存活数年,这使它们成为基于细胞的全身性酶替代疗法的一种有吸引力的方法。在这里,我们测试了基因工程、表达 IDUA 的 Tm 作为一种细胞疗法在 MPS I 免疫缺陷小鼠模型中的应用。我们的结果表明,单剂量的工程化 Tm 可使血液中可检测到的 IDUA 酶水平持续长达 22 周,并减少尿液中 GAG 的排泄。此外,工程 Tm 几乎能在所有测试组织中驻留,产生 IDUA 并导致心脏、肺、肝脏、脾脏、肾脏、骨髓和中枢神经系统中 GAG 水平的新陈代谢纠正,但仅观察到认知能力的极小改善。我们的研究表明,基因工程Tm有望成为基于细胞的酶替代疗法平台,用于治疗I型粘多糖病以及潜在的许多其他酶病和蛋白质缺乏症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Engineering memory T cells as a platform for long-term enzyme replacement therapy in lysosomal storage disorders.

Enzymopathy disorders are the result of missing or defective enzymes. Among these enzymopathies, mucopolysaccharidosis type I is a rare genetic lysosomal storage disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), which ultimately causes toxic buildup of glycosaminoglycans (GAGs). There is currently no cure and standard treatments provide insufficient relief to the skeletal structure and central nervous system (CNS). Human memory T (Tm) cells migrate throughout the body's tissues and can persist for years, making them an attractive approach for cellular-based, systemic enzyme replacement therapy. Here, we tested genetically engineered, IDUA-expressing Tm cells as a cellular therapy in an immunodeficient mouse model of MPS I. Our results demonstrate that a single dose of engineered Tm cells leads to detectable IDUA enzyme levels in the blood for up to 22 weeks and reduced urinary GAG excretion. Furthermore, engineered Tm cells take up residence in nearly all tested tissues, producing IDUA and leading to metabolic correction of GAG levels in the heart, lung, liver, spleen, kidney, bone marrow, and the CNS, although only minimal improved cognition was observed. Our study indicates that genetically engineered Tm cells hold great promise as a platform for cellular-based enzyme replacement therapy for the treatment of mucopolysaccharidosis type I and potentially many other enzymopathies and protein deficiencies.

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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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