The race is on to turn your body into a GLP-1 factory

People looking to lose weight and lower their blood sugar may someday be able to get a single injection that turns their cells into tiny factories churning out a protein that is essentially the active ingredient in drugs like Ozempic, Wegovy, Zepbound and Mounjaro.

That’s the ambition of two biotech startups, New York-based RenBio and Fractyl Health in Massachusetts. Both companies have completed initial tests showing that their approaches work, at least in mice, and both have started tests in larger animals — pigs and monkeys — to see whether their gene therapies can work in larger animals.

With continued success and enough funding, they hope to bring the therapies to human patients — although it may take years more research to prove that their ideas work and are safe.

Newer GLP-1 medications – available as injections and pills – have proven to be highly effective for weight loss, ushering in a new era of obesity treatment.

GLP-1, which stands for glucagon-like peptide-1, is a hormone made by the body that helps signal to the brain and the gut that it’s full and doesn’t need to eat any more. The new weight loss drugs mimic the action of this hormone by increasing the secretion of insulin to lower blood sugar. They also slow the movement of food through the digestive tract, which helps people feel full more quickly and for longer, and they work in the brain to reduce appetite.

In less than two years, the percentage of American adults using these meds for weight loss has roughly doubled, rising from 5.8% to 12%, according to a recent Gallup report. Their popularity may finally be making a dent in the nation’s obesity rate, which dropped from 39.9% in 2023 to 37% in 2025, according to Gallup.

But the medicines can be expensive, and up to half of users say they have side effects including nausea, vomiting and fatigue. Studies suggest that people need to continue using them to maintain their weight loss, but many people don’t love the idea of staying on them indefinitely. A recent study found that nearly two-thirds of people without diabetes who started GLP-1 drugs stopped within a year.

The next wave of research has sought to capitalize on the benefits of GLP-1s with fewer downsides. That’s where companies like Fractyl and RenBio come in.

Fractyl is presenting the latest results from its trial of a gene therapy called Rejuva in mice at the annual meeting of the Obesity Society, called ObesityWeek, which is being held in Atlanta this week.

RenBio shared its results from ongoing mouse studies as a preprint paper, meaning it has not been peer reviewed or accepted into a medical journal, last month. RenBio will also present updated findings at ObesityWeek.

Turning muscle cells into GLP-1 factories

RenBio calls its technology “Make Your Own,” and it’s a relatively simple idea. They use a plasmid — a ring of naked DNA — in saline solution.

DNA, which stands for deoxyribonucleic acid, carries the instructions that the body uses to build and constantly refurbish itself. It lives in the nucleus, or brain, of every cell as a twisting, double-sided ladder. The ladder is made up of four individual nucleic acids, like the letters that make up words in a book, strung together in long chains that spell out the instructions for proteins. The order of the letters tells the body how to make the proteins.

In RenBio’s case, the researchers spelled out the instructions to make a GLP-1 receptor agonist protein — essentially the same active ingredient in medicines like Ozempic and Mounjaro — and looped it into a small circle called a plasmid. They injected saline solution containing these plasmids into muscle tissue and used short electrical pulses — milliseconds long — to zap the muscle cells.

“It works really efficiently. Basically, the electrical pulses transiently make little pores in the cell membrane that allow the DNA rings to slip into the cell,” said Dr. Rachel Liberatore, president and chief scientific officer at RenBio.

From there, the plasmids migrate to the nucleus, where they hang out in the jelly-like cytoplasm. When the cell gets ready to translate its own DNA, the plasmid DNA is read and translated right alongside it. When the cell reads the instructions, it builds the GLP-1 receptor agonist protein and releases it into the body.

Liberatore said that although RenBio’s therapy uses a genetic technology, it’s not a traditional gene therapy: The researchers aren’t trying to fix a broken gene. Rather, they’re using the cell’s own machinery to turn it into a protein factory.

“The DNA we’re injecting, the plasmid DNA, doesn’t interfere with your own DNA in any way. So it doesn’t interfere with your own chromosomes. It doesn’t integrate. It’s not something you’re going to pass on to your children,” Liberatore said.

RenBio is also using this platform to make protein therapies that can be built in the same way, like antibodies to the Zika virus. The work is supported by the federal government’s Defense Advanced Research Project Agency, or DARPA, and the Biomedical Advanced Research and Development Authority, known as BARDA. It’s also supported by the Wellcome Trust, a health research foundation.

In RenBio’s most successful experiments, mice injected with the plasmids lost about 15% of their body weight, which was significantly more than mice in a placebo group. The loss was maintained for at least a year after they received the plasmid DNA.

In each formulation tested, the weight loss leveled off in mice treated with the plasmids. In essence, they hit a plateau. But that’s a good thing if you’re using a long-acting therapy, Liberatore said.

“We were actually quite happy to see that, because you don’t necessarily want continued weight loss for a year, a year and a half,” Liberatore said.

Glucose tolerance tests show that blood sugar was better regulated, too.

The researchers aren’t sure how long the plasmids may remain active. The idea is that a doctor might give their patients a shot every year or two.

“I think what our take on it is, it’s really ideally suited for the sort of maintenance phase that people are starting to talk about with GLP-1s,” Liberatore said.

The plasmid platform has also been tested on monkeys, and the researchers even used the device to inject themselves – albeit with pure saline, not with any plasmids.

RenBio hopes to begin testing its plasma platform to deliver instructions for making antibodies against the Zika virus in people next year.

Targeting cells to help the body make more GLP-1

Another company called Fractyl Health is taking a slightly different approach. It uses a more traditional gene therapy technique in which the outer shell of a small virus — called an adeno-associated virus — slips DNA into cells and givens them the instructions to make GLP-1.

In rare cases, when viruses are used to deliver genes, they can trigger an immune response in the body, leading to potentially dangerous inflammation, allergic reactions or organ damage. In other cases, gene therapy vectors like viruses may wind up where they’re not supposed to be and can introduce errors into the genomes of cells, which can lead to cancer.

The idea is that a single treatment delivered directly to the insulin-producing cells in the pancreas would never need to be repeated.

“Because we are delivering it locally, we believe that we will need a very low dose of this virus, which helps gives us confidence in the potential safety in people,” said Dr. Harith Rajagopalan, co-founder and CEO of Fractyl Health.

The researchers have tried this in mice and pigs, and both tests were successful, Rajagopalan said. But mice and pigs aren’t humans, and many therapies that have succeeded in lab animals have gone on to fail in people.

“There is promise, but much more data would be needed to consider human clinical trials, as it likely would be irreversible,” said Dr. Donald Kohn, a distinguished professor of microbiology, immunology and molecular genetics, at the Broad Stem Cell Research Center at the University of California – Los Angeles.

“The concern would be, the genetic change would be permanent so if there is over-expression … which may change with various states — weight loss, illness, aging, hormonal changes — it could cause problems from over-expression with no way to reverse, except remove the pancreas or treated muscle,” Kohn said in an email.

Kohn said there has long been a debate in gene therapy about whether it should be used for non-disease treatment, such as enhancement of height or muscle mass. In general, the feeling is that it should not be used for enhancements.

“This certainly is near that line between Medicine and enhancement and so I think that’s another reason that needs to be considered whether this is something that should be gone into,” Kohn said.

Fractyl says it has filed the regulatory paperwork in the US to start human trials.

“We anticipate seeing human data in the next year, in 2026,” Rajagopalan said.

Viruses are experts at infecting cells, so scientists use that capability to slip DNA into a cell, so the cell can start building the proteins the researchers want it to build – in this case, GLP-1.

Gene therapy like this can be risky, however, so in order to minimize the risk, the researchers designed their DNA to recognize the promoter sequence for insulin. Promoter sequences are short stretches of DNA that tell the cell’s copying machinery where a new protein starts. It acts like an on/off switch in the DNA.

By having the DNA sequence for GLP-1 recognize the insulin promoter, the researchers tied the function of their sequence to the production of insulin, another hormone that helps regulate blood sugar.

That means only cells that make insulin will also make GLP-1, limiting the dose that’s delivered to the body.

It also creates a way to dial up or down the volume of extra GLP-1. When a mouse eats a high-fat, high-calorie meal, its body will make more insulin but also more GLP-1, to guard against weight gain. When it eats a more moderate serving of its normal chow, it won’t make as much GLP-1, so it won’t lose weight when it doesn’t need to.

In mice, the results have been encouraging, said Dr. Randy Seeley, a professor at the University of Michigan who studies hormone signaling as it relates to type 2 diabetes and obesity. Fractyl hired Seeley to test the gene therapy, and he owns stock options in the company.

Obese mice that were treated with the gene therapy, which Fractyl calls Rejuva, lost about 20% of their body weight within three weeks.

“It outperformed semaglutide,” the active ingredient in Ozempic and Wegovy, Rajagopalan said.

When researchers treated normal-weight mice with the gene therapy and then fed them a high-fat diet, the mice did not gain weight. Their blood sugar also stayed normal.

When they gave the gene therapy to lean mice who ate their normal diet, the lean mice didn’t lose excessive amounts of weight. They also didn’t seem to develop dangerously low blood sugar, suggesting that it might be safe to use to prevent obesity as well as treat and maintain it.

It might also be a way to prevent diabetes.

Rajagopalan envisions a day when it might be possible to identify people at risk of obesity, because of a family history or other factors, and give them gene therapy to prevent that fate.

In a food environment where processed foods have been engineered to trick the brain into eating unhealthy amounts, he sees this gene therapy as potentially helping people regain control over their appetite and health.

“Food is cheaper per calorie and more widely available than at any point in human history,” Rajagopalan said. “We’re just not built to make enough GLP-1 for the world around us.”

The solution, he said, may be helping the body make more of its own.

“There’s a long way to go before you get there, and we can’t minimize the work involved. I mean, that’s equivalent to saying we’re going to colonize Mars, in terms of the magnitude of effort involved to get there,” Rajagopalan said. “But why not aspire to aspire to that?”

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