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转基因小鼠中LPA的细胞因子基编辑避免了大量的删除

Marcel A Chuecos¹, So Hyun Park², Madhvi M Bhakta³

¹Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, 77030. USA; Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX, 77030. USA.

Molecular therapy : the journal of the American Society of Gene Therapy

|March 5, 2026

概括

细胞酶基编辑 (CBE) 提供了一种新的方法来降低脂蛋白 (Lp) 水平. 这种基因组编辑策略有效地减少了小鼠中的Lp(a),而不会造成显著的有害基因组删除,与CRISPR/Cas9.9不同.

科学领域:

心血管遗传学心血管遗传学
基因治疗基因治疗
分子生物学分子生物学

背景情况:

脂蛋白 (Lp) 是心血管疾病的基因决定风险因素,影响约20%的人口.
目前对升高的Lp (a) 的治疗选择有限,这突显了对新型干预措施的需求.
基因组编辑为降低Lp(a) 提供了一个潜在的一次性解决方案,但像CRISPR/Cas9这样的传统方法可能会导致大量的基因组删除.

研究的目的:

调查TadA衍生的细胞因子基编辑 (CBE) 的有效性和安全性,以降低脂蛋白 (Lp) 水平.
评估通过辅助性腺病毒 (HDAdV) 和腺相关病毒 (AAV) 载体传递的CBE的潜力.
在CBE针对LPA基因后评估基因组完整性.

主要方法:

利用通过HDAdV和AAV载体传递的TadA衍生的细胞因子基编辑 (CBE),在LPA基因中引入过早停止编码子.
使用单分子独特分子标识符 (UMI) 的 SMRT-seq 来量化基因组删除事件.
在LPA转基因小鼠模型中比较CBE的基因组影响与CRISPR/Cas9切割.

主要成果:

在LPA转基因小鼠中,CBE强大而持久地降低了循环的阿波利波蛋白 (apo) 水平.
在针对单个LPA位点时,CBE没有诱导大型基因组删除,并且在多个位点中导致<4%的大型删除.
CRISPR/Cas9切割LPA主要导致大量的删除,这表明基因组不稳定性风险更高.

结论:

在相关的小鼠模型中,TadA衍生CBE是一种有效的策略,用于持续降低apolipoprotein (apo) 的水平.
与CRISPR/Cas9.9相比,CBE在很大程度上保持了基因组完整性,证明了有利的安全性.
这项研究确立了CBE作为一个有前途的基因组编辑工具,用于管理高脂蛋白 (Lp) 和心血管疾病风险.

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