Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes
Abstract 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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Communications Medicine |
| Online Access: | https://doi.org/10.1038/s43856-025-00959-8 |
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| author | Jun Hirose Emi Aizawa Shogo Yamamoto Shigenori Iwai Keiichiro Suzuki |
| author_facet | Jun Hirose Emi Aizawa Shogo Yamamoto Shigenori Iwai Keiichiro Suzuki |
| author_sort | Jun Hirose |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-2370bbbc61d848da9bb934494756aae6 |
| institution | Kabale University |
| issn | 2730-664X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Medicine |
| spelling | doaj-art-2370bbbc61d848da9bb934494756aae62025-08-20T03:46:13ZengNature PortfolioCommunications Medicine2730-664X2025-07-015111110.1038/s43856-025-00959-8Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetesJun Hirose0Emi Aizawa1Shogo Yamamoto2Shigenori Iwai3Keiichiro Suzuki4Graduate School of Engineering Science, The University of OsakaGraduate School of Engineering Science, The University of OsakaGraduate School of Engineering Science, The University of OsakaGraduate School of Engineering Science, The University of OsakaGraduate School of Engineering Science, The University of OsakaAbstract 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.https://doi.org/10.1038/s43856-025-00959-8 |
| spellingShingle | Jun Hirose Emi Aizawa Shogo Yamamoto Shigenori Iwai Keiichiro Suzuki Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes Communications Medicine |
| title | Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes |
| title_full | Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes |
| title_fullStr | Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes |
| title_full_unstemmed | Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes |
| title_short | Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes |
| title_sort | targeted in vivo gene integration of a secretion enabled glp 1 receptor agonist reverses diet induced non genetic obesity and pre diabetes |
| url | https://doi.org/10.1038/s43856-025-00959-8 |
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