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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月9日

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  • Jun Hirose,
  • Emi Aizawa,
  • Shogo Yamamoto,
  • Shigenori Iwai,
  • Keiichiro Suzuki

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.