摘要
背景:I型粘多糖贮积症(MPS I)是一种由α-L-艾杜糖醛酸酶(IDUA)缺乏引起的遗传性疾病。现有的治疗方法不能有效改善疾病的所有体征和症状。目的:在本研究中,我们评估了与质粒 pIDUA(含有 IDUA 基因)相关的阳离子纳米乳反复静脉给药的转染效率。方法:阳离子纳米乳液由1,2-二油酰-sn-甘油-3-磷酸乙醇胺(DOPE)、1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-N-(氨基[聚乙二醇]-2000)组成( DSPE-PEG)、1,2-dioleoyl-sn-glycero-3-trimethylammonium propane (DOTAP)、中链甘油三酯、甘油和水,通过高压均质化制备,并反复施用于 MPS I 小鼠用于 IDUA生产和基因表达。结果:在所有分析的器官中观察到 IDUA 表达显着增加,与我们之前的报告相比,当小鼠接受相同剂量的单次给药时,IDUA 活性倾向于随着重复给药而增加。此外,通过生化和组织学分析评估,GAG 部分从器官中清除。不存在炎症浸润、坏死或细胞凋亡增加的迹象。此外,CD68 的免疫组织化学显示,与未处理的 MPS I 小鼠相比,处理后的巨噬细胞存在减少。结论:这些结果表明,在 MPS I 小鼠模型中,重复给药可以提高阳离子复合物的转染效率,而不会显着增加毒性。
关键词: 阳离子纳米乳剂、基因治疗、I型粘多糖贮积症、非病毒载体、质粒、酶替代疗法。
图形摘要
Current Gene Therapy
Title:Gene Therapy of Mucopolysaccharidosis Type I Mice: Repeated Administrations and Safety Assessment of pIDUA/Nanoemulsion Complexes
Volume: 21 Issue: 5
关键词: 阳离子纳米乳剂、基因治疗、I型粘多糖贮积症、非病毒载体、质粒、酶替代疗法。
摘要:
Background: Mucopolysaccharidosis type I (MPS I) is an inherited disorder caused by α-L-iduronidase (IDUA) deficiency. The available treatments are not effective in improving all signs and symptoms of the disease.
Objective: In the present study, we evaluated the transfection efficiency of repeated intravenous administrations of cationic nanoemulsions associated with the plasmid pIDUA (containing IDUA gene).
Methods: Cationic nanoemulsions were composed of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(amino[polyethylene glycol]- 2000) (DSPE-PEG), 1,2-dioleoyl-sn-glycero-3-trimethylammonium propane (DOTAP), medium- chain triglycerides, glycerol, and water and were prepared by high-pressure homogenization and were repeatedly administered to MPS I mice for IDUA production and gene expression.
Results: A significant increase in IDUA expression was observed in all organs analyzed, and IDUA activity tended to increase with repeated administrations when compared to our previous report when mice received a single administration of the same dose. In addition, GAGs were partially cleared from organs, as assessed through biochemical and histological analyzes. There was no presence of inflammatory infiltrate, necrosis, or signs of an increase in apoptosis. Furthermore, immunohistochemistry for CD68 showed a reduced presence of macrophage cells in treated than in untreated MPS I mice.
Conclusion: These sets of results suggest that repeated administrations can improve transfection efficiency of cationic complexes without a significant increase in toxicity in the MPS I murine model.
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Cite this article as:
Gene Therapy of Mucopolysaccharidosis Type I Mice: Repeated Administrations and Safety Assessment of pIDUA/Nanoemulsion Complexes, Current Gene Therapy 2021; 21 (5) . https://dx.doi.org/10.2174/1566523221666210126151420
DOI https://dx.doi.org/10.2174/1566523221666210126151420 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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