New weight-loss medications have received worldwide attention in recent years. Active ingredients like semaglutide, tirzepatide, or orforglipron help many people lose significant weight. They work by mimicking the intestinal hormone GLP-1, which creates feelings of satiety in the body. However, these medications must be injected weekly or taken daily as tablets. Their effect ends when discontinued, and the lost weight often returns.
Researchers are therefore working on a new idea: gene therapy that allows the body to produce GLP-1 agonists itself. The goal is permanent hormone release without weekly injections or daily tablets. Companies like Fractyl Health and RenBio rely on so-called adeno-associated viruses (AAV). These viruses transport the GLP-1 gene into specific cells, which should then produce the hormone.
Safety Concerns with AAV Gene Therapies
Despite promising approaches, there are important safety concerns with AAV-based gene therapies. In 2025, three patients with muscular dystrophy died from acute liver failure after treatment with AAV gene therapies from Sarepta Therapeutics. While this doesn't mean GLP-1 gene therapies automatically carry the same risks, it shows how carefully one must handle AAV viruses.
Another problem is that the activity of introduced genes can no longer be fully controlled. Once the body starts producing GLP-1, the amount cannot be easily regulated. While companies emphasize that their gene therapy could deliver more consistent hormone levels than current weight-loss injections, comprehensive long-term studies are still needed.
New Research Approaches
Two recent studies show how innovative concepts could work as alternatives to AAV-based GLP-1 gene therapy. Researchers at the University of Massachusetts developed a system based on lipid nanoparticles. These tiny fat globules transport DNA fragments into fat cells under the skin, where they cause cells to produce GLP-1 receptor agonists like GLP-1 and exendin-4 themselves. In trials with overweight mice, a single injection of lipid nanoparticles led to 14 to 20 percent weight loss that persisted for months.
Another team from Japan used an even more precise method: they combined lipid nanoparticles with the genome-editing technique CRISPR-Cas. With this approach, the research team built the exendin-4 gene directly into the liver's albumin gene. This caused liver cells to permanently produce the hormone and release it into the bloodstream. The treated mice showed improved blood sugar levels and reduced weight gain over 28 weeks.
However, this CRISPR-based method also carries risks. Apart from irreversibility, genome editing can cause unwanted changes at other locations in the genome, so-called off-target effects. These could lead to unpredictable side effects in the long term, which is why intensive safety testing is necessary here as well.
Significance for Switzerland
The topic plays a special role for Switzerland. The proportion of people affected by obesity increased from 5 percent in 1992 to 12 percent in 2022. At the same time, modern GLP-1 medications are in high demand, repeatedly leading to supply shortages.
Swissmedic generally treats gene therapies as a high-risk area, which means approval would have to undergo very strict testing. Gene therapies against beta-thalassemia and sickle cell disease are already approved in Switzerland. However, these interventions correct genetic defects that would otherwise lead to severe disease progression with few therapeutic alternatives. GLP-1 gene therapies, on the other hand, target obesity – a health problem for which various treatment options already exist. This raises questions about prioritization and appropriate use of gene therapies.
References
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2. Franco JVA, Guo Y, Varela LB, et al. Tirzepatide for adults living with obesity. Cochrane Database of Systematic Reviews 2025, Issue 10. Art. No.: CD016018. doi: 10.1002/14651858
3. Rosenstock, JulioManghi, Federico Perez et al. Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial. The Lancet, Volume 0, Issue 0 (2026). doi: 10.1016/S0140-6736(26)00202-3
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9. Hirose, J., Aizawa, E., Yamamoto, S. et al. Targeted in vivo gene integration of a secretion-enabled GLP-1 receptor agonist reverses diet-induced non-genetic obesity and pre-diabetes. Commun Med 5, 269 (2025). doi: 10.1038/s43856-025-00959-8
10. https://www.swissdocu.ch/de/news/107-allgemeine-informationen/2705-schweizerische-gesundheitsbefragung-neue-daten-zu-uebergewicht-und-adipositas (accessed March 2, 2026)
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