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Alnylam discovers mutations in stomach fat gene that could protect against abdominal obesity

The findings support the potential for the INHBE gene to be evaluated as a novel therapeutic target for the treatment of cardiometabolic disease


Alnylam Pharmaceuticals and its collaborators have identified mutations in the INHBE gene associated with protection against abdominal obesity and metabolic syndrome, a condition affecting more than 20% of adults worldwide, the company announced.

The data published in the journal Nature Communications demonstrates that rare mutations in the liver-expressed INHBE gene are linked with lower waist-to-hip ratio adjusted for body mass index (WHRadjBMI), a surrogate for abdominal fat that is causally linked to type 2 diabetes and coronary heart disease.

Cardiometabolic diseases are the number one cause of death in the world, Alnylam stated, with an estimated 47 million people in the US alone living with some form of cardiometabolic diseases. Despite availability of well-established treatments for these diseases, the substantial mortality associated with this group underpins an unmet medical need for new therapeutic options.

The findings support the potential for INHBE to be evaluated as a novel therapeutic target for the treatment of cardiometabolic disease. The company plans to pursue a development candidate for INHBE and its gene product, Activin E.

As a member of the transforming growth factor (TGF) beta superfamily, Activin E is a secrete peptide that is thought to play a role in the control of metabolism through brown adipose tissue, suggesting that activin E has a high potential for obesity therapy.

The discovery used whole exome-sequencing data from UK Biobank, from more than 360,000 individuals or European ancestry with WHRadjBMI, revealing ‘loss of function’ in INHBE as a novel genetic factor contributing to a healthier fat distribution.

Paul Nioi, vice president, Discover and Translational Research, and leader of Alnylam’s Human Genetics Group, said: "We are thrilled that our investment in genetic databases like UK Biobank is proving to be fruitful in identifying novel targets in highly prevalent diseases with continued unmet need.

“There is a well-established causal link between increased waist-to-hip ratio and a person’s risk of cardiometabolic conditions… The results of this exome-wide analysis suggest that targeting INHBE is predicted to have broad beneficial effects on all facets of metabolic syndrome with potential reductions in the risk of type 2 diabetes and coronary heart disease. We are currently testing this hypothesis, with the goal of pursuing a development candidate targeting INHBE in the near future.”

Article by
Emily Kimber

29th July 2022

From: Research, Healthcare



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