GLP-1 therapies show potential for treating rare genetic disorder Bardet-Biedl syndrome

A Monell Chemical Senses Center study published this week in the Journal of Clinical Investigation offers renewed hope for individuals living with Bardet-Biedl Syndrome (BBS), a rare genetic disorder characterized by early-onset obesity, compulsive eating, and cognitive impairments.

The Monell team and colleagues identified that GLP-1 receptor agonists, a class of drugs currently used to treat type 2 diabetes and obesity, as a promising therapeutic for managing the metabolic complications associated with BBS.

They used a genetically engineered mouse model of BBS that displayed the hallmark features of the condition, including excessive eating, impaired glucose regulation, behavioral deficits, and disrupted hormonal function. Remarkably, treatment with a GLP-1 receptor agonist (such as Ozempic and Wegovy) significantly reduced food intake, caused weight loss, improved glucose tolerance, and normalized metabolic hormone levels in the animals.

“Our findings suggest that GLP-1-based therapies effectively target gut and brain pathways involved in feeding and metabolism, even in the context of a complex genetic disorder like BBS,” said first author Arashdeep Singh, Ph.D., former Monell Research Associate. “This offers a much-needed treatment option for an underserved population.” Singh now holds the position of Scientist at Research Diets, Inc. located in New Brunswick, NJ.

Unique model gives hope

The BBS mice are a fair approximation of the disease in humans. Specifically, their white fat tissue had immune cells more prone to inflammation and dysfunctional anti-inflammatory T cells, suggesting a different mechanism for weight gain compared to typical obesity animal models.

In addition, BBS mice exhibited enlarged pancreatic islet cells, suggesting defective control of insulin levels in the circulatory system. The dysregulated molecular pathways they found also confirmed the cell-to-cell communication defects with insulin, leptin, and other hormones, yet at the same time preserving GLP-1R’s normal function.

Crucially, when BBC mice were given a GLP-1R, it effectively alleviated overeating, lessened body weight gain, improved glucose tolerance, and normalized circulating metabolic hormones.

Overall, the study establishes two reasons for hope for a BBS treatment: one, BBS mice are a valuable model of this rare disease to understand its pathology and develop better treatments and two, the team’s findings highlight the therapeutic potential of GLP-1R agonists for managing BBS-associated metabolic dysregulation, warranting further investigation for clinical application.

Despite the promise of this research, real-world access to treatment remains a major challenge. The authors note that in conversations with physicians, they encountered hesitancy in prescribing GLP-1 therapies to BBS patients, largely due to a lack of clinical trial data. Many patients, especially in the United States, also face additional systemic barriers, such as restrictive health insurance coverage rules. BBS has a prevalence in North America and Europe of 1 in 140,000 to 1 in 160,000 newborns.

“This study represents a significant step forward in closing the treatment gap for BBS and demonstrates how targeting central satiety pathways with GLP-1 therapies may benefit patients whose conditions have long lacked effective medical options,” said senior author Guillaume de Lartigue, Ph.D., Monell Associate Member.