人类囊性纤维化模型中的肺组织优化基因编辑,在局部应用脂质纳米颗粒后进行
Belal Tafech1, Tiffany Carlaw1, Gaurav Sadhnani2
1Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver V6T 1Z3, BC, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
概括
针对囊性纤维化 (CF) 的CRISPR基因编辑面临着交付挑战. 优化的脂质纳米颗粒 (LNP) 显示出希望,在CF患者细胞中实现12%的纠正,为CFTR突变提供了潜在的新治疗方法.
科学领域:
- 生物技术是生物技术.
- 基因工程是一种基因工程.
- 肺部医学 肺部医学
背景情况:
- 囊性纤维化 (CF) 是一种严重的单一性肺病,由CFTR基因突变引起.
- 克里斯普尔基因编辑为CF治愈提供了潜力,但高效的肺部输送是一个障碍.
研究的目的:
- 开发和优化肺向基因编辑策略,使用脂质纳米颗粒 (LNP) 治疗囊性纤维化.
- 评估基因编辑效率在日益复杂的人类和患者衍生的CF模型中.
主要方法:
- 系统地优化LNP,包括脂质,货物,导向RNA和编辑器比率.
- 在2D模型,3D仿生支气管上皮组织模型和CF患者衍生细胞中进行测试.
- 评估先天性免疫反应和粘菌性预处理的影响.
主要成果:
- 在2D模型中,在模型基因 (HPRT) 中实现了~50%的编辑效率.
- 在3DCF支气管模型中,编辑效率下降到~5%;在dornase alpha预处理时增加到~12.7%.
- 在CFTR R1162X突变的CF患者细胞中使用优化的LNP证明了~12%的基因水平校正.
结论:
- 在CF的临床基因编辑应用中,优化基因货物和运输车辆 (LNP) 是至关重要的.
- 这项研究提供了现实的人类支气管模型中基因编辑率的见解,为局部治疗铺平了道路.
- 开发的LNP策略为目前无法治疗的CFTR突变提供了潜在的治疗途径.
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