Early Promise for Genetic Therapies in Obesity Treatment

Recent advancements in genetic therapies suggest a promising future in combating obesity, driven by early-stage research from several biopharma companies and academic institutions. Preclinical findings indicate that these therapies could potentially facilitate weight loss akin to that achieved by GLP-1 agonists, such as semaglutide, but without some of the associated side effects like muscle loss.

Paul Bolno, CEO of Wave Life Sciences, shared that gene therapy might enable once or twice-yearly dosing, focusing on fat reduction without affecting muscle mass. This approach could offer a significant advantage over current treatments, particularly for the rapidly growing obese population. The World Obesity Federation's World Obesity Atlas 2024 highlights the severity of the issue, estimating that around 1 billion people currently suffer from obesity globally. If trends persist, by 2035, half of the world's adults could be obese, with an alarming economic impact exceeding $4 trillion annually.

Companies like Wave, Regeneron, and Alnylam are exploring this market by targeting specific genes to combat obesity. Meanwhile, researchers at the University of Barcelona are developing ex vivo gene therapy strategies. Although these products have not yet reached human trials, there is optimism that they could eventually provide results comparable to or better than GLP-1 agonists now prevalent in the market.

GLP-1 agonists have shown efficacy in reducing weight in various patients. For instance, a review encompassing 76 trials with over 39,000 participants demonstrated significant improvements in blood glucose levels and weight loss ranging from 16 to 30 pounds in individuals with type 2 diabetes. However, this weight loss often comes with muscle loss, which poses risks, especially for older patients.

A recent mouse study by Wave Life Sciences revealed promising results. Using a N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) to target the INHBE gene, researchers achieved a 56% reduction in visceral fat without muscle mass loss. Further analysis of whole-genome sequences from the UK Biobank indicated that individuals with loss-of-function variants in this gene exhibited favorable traits—low waist-to-hip ratio, low visceral fat, and reduced levels of LDL cholesterol and triglycerides. This suggests that INHBE gene silencing in humans could potentially induce weight loss similar to semaglutide.

Wave plans to initiate clinical trials in 2025 involving healthy, overweight participants, with potential follow-up studies in obese patients if initial trials are successful. Bolno speculates that once or twice-yearly treatments may be feasible based on current data.

INHBE is not the sole gene linked to obesity. Genome-wide association studies have identified around 250 genes associated with the condition, presenting numerous potential targets. Regeneron is honing in on rare genetic mutations in the GPR75 gene, which appear to protect against obesity. A study of 650,000 individuals, including data from the UK Biobank, found that those with inactive copies of the GPR75 gene weighed an average of 12 pounds less and faced a 54% lower risk of obesity. Regeneron is pursuing three programs targeting GPR75, including collaborations with Alnylam, AstraZeneca, and in-house antibody approaches.

Additionally, University of Barcelona researchers are investigating ex vivo gene therapy to create cells that produce the CPT1AM protein, crucial for fatty acid oxidation in mitochondria, thereby enhancing fat-burning capacity. Early mouse studies reported significant reductions in weight and improvements in metabolic health markers. The research team is now optimizing this approach before advancing to human trials.

Despite the potential of gene-based therapies, obesity is a multifaceted issue involving numerous genetic and epigenetic factors. While gene therapy might offer a solution for single-gene-related cases, polygenic obesity presents a more complex challenge. Current technology does not yet allow us to target multiple genes simultaneously, and the economic, ethical, and unintended genetic consequences must be considered.

Though gene therapy may not be a universal solution, it holds promise for specific cases and could serve as a last resort for patients unresponsive to other treatments. By laying the groundwork for addressing multifactorial diseases, these pioneering efforts could lead to more effective interventions in the future.