Gene Editing Unlocks DIY Weight-Loss Drug Delivery
One gene-editing injection helped mice make their own weight-loss drug for over six months.
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Instead of injecting weight-loss drugs every week, what if your body could make its own?
In a study from the University of Osaka, researchers used genome editing to engineer mouse liver cells to secrete exenatide, a drug used to treat obesity and pre-diabetes.
Published in Communications Medicine, the mice showed sustained weight control and improved glucose metabolism for over six months after one treatment.
Why genome editing may help solve weight loss treatment limits
Obesity and Type 2 diabetes are major global health problems. They’re driven by complex combinations of diet, environment and genetics. That complexity makes them hard to treat using traditional gene therapy, which works best when a single faulty gene is to blame.
One class of drugs, glucagon-like peptide-1 (GLP-1) receptor agonists such as exenatide, helps with weight loss and blood sugar control. These drugs mimic a hormone that suppresses appetite and boosts insulin release; however, they have a short half-life. Patients need regular injections – sometimes weekly, sometimes daily – which can be hard to stick with over the long term.
“These medications do not stay in the body long, meaning they typically have to be injected weekly, or even daily, to maintain consistent therapeutic levels of the drug,” said senior author Dr. Keiichiro Suzuki, a specially designated professor from the University of Osaka.
Genome editing, especially tools such as CRISPR, has had major success in treating rare diseases caused by single mutations. But complex conditions like obesity don’t have a clear genetic target, limiting what current gene-editing approaches can do. Meanwhile, biologics – injectable protein drugs – offer some help but come with their own problems: high cost, frequent dosing and side effects from long-term use.
Instead of fixing a broken gene, Suzuki and the team used genome editing to insert a new gene, which makes exenatide, into mouse liver cells. The goal: a one-time treatment that turns the liver into a long-lasting source of the drug, avoiding the need for injections.
How genome editing enabled sustained weight-loss drug delivery
The researchers used a genome editing method, called homology-independent targeted insertion (HITI), to insert the modified exenatide-encoding gene. They chose the albumin gene locus, a high-expression site in liver tissue, to drive continuous production of the drug. The exenatide-encoding gene was tweaked to include a signal peptide and a cleavage site, which helped the cells release it into the bloodstream.
To get the editing components into the liver, they packaged the Cas9 enzyme and donor DNA into lipid nanoparticles, similar to those used in some mRNA vaccines. A single intravenous injection was enough to deliver the payload.
In early tests with cultured liver cells, the modified exenatide was secreted successfully and worked just as well as the commercial version. The team then ran long-term tests in mice with diet-induced obesity and pre-diabetes.
Over a period of 28 weeks, they monitored exenatide levels in the blood, food intake, body weight and several markers of glucose metabolism.
“We found that these genome-edited mice produced high levels of exenatide that could be detected in blood for several months after introduction of the gene,” said Suzuki.
The mice ate less, gained less weight and had better blood sugar control. Their insulin sensitivity improved, and their HbA1c levels dropped.
The treatment also didn’t cause liver damage or interfere with normal GLP-1 signaling.
Compared to mice receiving continuous exenatide via infusion, the genome-edited mice showed similar or better results – without the need for repeated dosing.
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A second dose further increased exenatide levels, suggesting the therapy could be tuned with repeat administration if needed.
What genome editing for weight loss could mean in the future
The study shows that a one-time edit can turn the liver into a steady source of a therapeutic protein, in this case exenatide. This could reduce or replace the need for repeated injections, something that could apply to other conditions managed with biologic drugs, such as inflammatory or heart disease.
“We hope that our design of a one-time genetic treatment can be applied to many conditions that do not have exact genetic causes,” said Suzuki.
Still, the approach had limitations. The editing success rate in the liver was low, with only ~1% of cells taking up the gene. Although that was enough to see a clear therapeutic effect, thanks to the liver’s strong protein production, the same strategy might not work as well in other tissues.
It’s also unclear how long the effects would last in humans or how the immune system might react over time to constant low-level exenatide exposure.
The next step is to test the treatment in other animal models, including ones that more closely mimic human obesity. The researchers also plan to refine the editing process.
If these hurdles can be cleared, genome editing could become a practical tool for managing chronic diseases that don’t have a clear genetic cause.
Reference: Hirose J, Aizawa E, Yamamoto S, Iwai S, Suzuki K. Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes. Comms Med. 2025;5(1):269. doi: 10.1038/s43856-025-00959-8
This article is a rework of a press release issued by the University of Osaka. Material has been edited for length and content.
