Hirose Jun, Aizawa Emi, Yamamoto Shogo, Iwai Shigenori, Suzuki Keiichiro
Graduate School of Engineering Science, The University of Osaka, Osaka, Japan.
Institute for Advanced Co-Creation Studies, The University of Osaka, Osaka, Japan.
Commun Med (Lond). 2025 Jul 9;5(1):269. doi: 10.1038/s43856-025-00959-8.
In vivo genome editing offers a long-term therapeutic approach for monogenic diseases by directly modifying genetic sequences. However, its application to non-monogenic, noncommunicable diseases, which are the leading causes of global mortality, remains limited due to the lack of well-defined genetic targets.
We developed an in vivo genome-editing approach to introduce a gene encoding the glucagon-like peptide-1 (GLP-1) receptor agonist Exendin-4, modified with a secretion signal peptide. Mice with obesity and pre-diabetic conditions received a single administration of genome editing. Blood Exendin-4 levels, food intake, body weight, and metabolic parameters were monitored over several months.
Here we show that in vivo genome editing enables sustained Exendin-4 secretion from liver cells, leading to prolonged elevation of Exendin-4 levels in the bloodstream. Treated mice exhibited reduced food intake, attenuated weight gain, and improved glucose metabolism and insulin sensitivity without detectable adverse effects.
This study demonstrates that a single administration of genome editing can achieve sustained therapeutic peptide secretion, providing a potential strategy for treating complex diseases without defined genetic causes.
体内基因组编辑通过直接修饰基因序列为单基因疾病提供了一种长期治疗方法。然而，由于缺乏明确的遗传靶点，其在作为全球主要死亡原因的非单基因、非传染性疾病中的应用仍然有限。
我们开发了一种体内基因组编辑方法，以引入一个编码胰高血糖素样肽-1（GLP-1）受体激动剂艾塞那肽-4的基因，该基因用分泌信号肽进行了修饰。患有肥胖症和糖尿病前期的小鼠接受了单次基因组编辑给药。在几个月内监测血液中的艾塞那肽-4水平、食物摄入量、体重和代谢参数。
我们在此表明，体内基因组编辑能够使肝细胞持续分泌艾塞那肽-4，导致血液中艾塞那肽-4水平长期升高。经治疗的小鼠食物摄入量减少，体重增加减缓，葡萄糖代谢和胰岛素敏感性得到改善，且未检测到不良反应。
本研究表明，单次基因组编辑给药可实现治疗性肽的持续分泌，为治疗无明确遗传病因的复杂疾病提供了一种潜在策略。
