Genetic therapies could help fight obesity, if early research at a few biopharma organizations and universities pans out. Preclinical studies indicate weight loss similar to that seen with GLP-1 agonists like semaglutide is possible but without some of the side effects, including muscle loss.
“With our investigational therapy, we see the potential for once-to-twice a year dosing . . . and to reduce fat, not reduce muscle,” said Paul Bolno CEO of Wave Life Sciences, which is conducting preclinical investigations into a siRNA product for obesity.
Obesity has become a global epidemic, affecting approximately 1 billion people, according to the World Obesity Federation’s World Obesity Atlas 2024. By 2035, if current trends continue, half of the world’s adults may be obese, with the projected annual global economic impact exceeding $4 trillion.
In addition to Wave, Regeneron and Alnylam are looking to tap into this market by silencing or knocking down specific genes to protect against obesity. Elsewhere, researchers at the University of Barcelona are developing an ex vivo gene therapy approach. No such products have made it to human testing yet, but the players in the field say they’ve got a real shot at providing results comparable to or even better than the GLP-1 agonists now flooding the market.
Genetic Obesity Targets
GLP-1 agonists are proving effective at reducing weight in a number of patients. For example, a review of 76 trials and more than 39,000 people shows significant improvements in blood glucose levels as well as weight loss ranging from 16 to 30 lbs in individuals with type 2 diabetes. Another study in non-diabetic individuals also reports substantial weight loss. This weight loss, however, comes at the expense of muscle loss, which can have serious consequences, particularly for elderly patients.
In a recent mouse study from Wave, a N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) successfully knocked down the INHBE transcript to reduce fat while preserving muscle. “The mice lost no muscle mass but had a 56% reduction in visceral fat,” Bolno told BioSpace.
The INHBE loss-of-function mutation was identified through the UK Biobank, which sequences and stores whole genomes. People with INHBE loss-of-function variants, Bolno said, exhibited “a low waist-to-hip ratio, low visceral fat, low levels of low-density lipoprotein (LDL) cholesterol and triglycerides.”
Wave plans to launch clinical trials in the first quarter of 2025 with healthy, overweight patients. If those are successful, the study may be repeated with obese patients. Based on results to date, Bolno speculated that once- or twice-yearly treatment may be possible.
Of course, INHBE isn’t the only gene associated with obesity. Genome-wide association studies have identified approximately 250 such genes. The involvement of so many genes creates a plethora of potential targets.
Regeneron is focusing on rare genetic mutations in the GPR75 gene that disable it and thereby protect against obesity. A 650,000-person study, which included data from the UK Biobank, identified those loss of function mutations in 1 of every 3,000 people studied. In that study, people with one or more inactive copies of the GPR75 gene weighed an average of 12 pounds less and had a 54% lower risk of obesity than those without the mutation.
Regeneron has three programs underway to target GPR75: a siRNA collaboration with Alnylam, a small molecule approach with AstraZeneca and an in-house antibody approach.
Meanwhile, researchers at the University of Barcelona are investigating ex vivo gene therapy as a way to create, and then implant, cells that produce the CPT1AM protein, which regulates fatty acid oxidation in the mitochondria. Their goal is to increase the body’s ability to burn fat.
Working with obese mice, senior researcher Laura Herrero reported significant reductions in weight, fatty liver, cholesterol and glucose levels. She and her team are now working to optimize the approach before moving into human testing.
The Outlook for Gene-Based Weight Loss Therapies
Ending obesity isn’t as straightforward as silencing one or two genes. Most cases of obesity involve several different genes and are also related to epigenetics. For instance, endocrine disruptors, high-energy foods and a sedentary lifestyle can all contribute to obesity.
“If there is a mutation in a single gene causing the obesity—and there are cases, such as leptin or MC4R deficiency—then gene therapy and gene editing is, in principle, possible,” Giles S.H. Yeo, a professor of molecular neuroendocrinology at the University of Cambridge, told BioSpace in an email.
“The issue with polygenic obesity is that, first, it involves more than a thousand loci,” Yeo continued. “Second, most of the changes are non-coding, so determining which is the causative polymorphism is tough. Finally, the technology we have today does not allow us to target more than one or two genes or gene products.”
For that reason, gene therapy won’t be a solution for every obese person. It is most likely for cases caused by a single gene or gene variant. For those, gene therapy . . . “might be considered as a last resort in patients who are not suitable for pharmacotherapy, and in whom other treatment approaches have failed,” Anke Hinney of the University of Duisburg-Essen, in Germany, and colleagues wrote in Nature Reviews Endocrinology.
Additionally, developing gene therapy for obesity is more than a scientific challenge, of course. “High costs, potential unintended genetic consequences and ethical concerns around genomic editing must also be addressed,” Aaron Erez, a board-certified, private-practice physician specializing in functional medicine, told BioSpace via email.
Yeo suggested that targeting the central nervous system with other therapies—GLP-1 agonists, for instance—may be a better approach. The reason, he explained in a 2021 paper in Nature, is that aspects of the central nervous system “control the hedonic aspects of food intake that are major drivers of obesity.” And, as he told BioSpace, “all of the current class of GLP-1-based anti-obesity therapeutics do, indeed, target the brain for their weight-loss effects.”
Nonetheless, research studying the possible efficacy of gene therapies that target obesity “lay[s] the groundwork for tackling multifactorial diseases,” Erez said, “and could pave the way for more effective interventions.”
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https://www.biospace.com/article/genetic-therapies-show-early-promise-in-treating-obesity-/
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