New Genetic Target Discovered by Regeneron could be Game-Changer for NASH

 Last week, the Regeneron Genetics Center shared exciting results from a study investigating the role of the CIDEB gene in liver disease. The center’s researchers have demonstrated a potential link between loss-of-function mutations in the gene and protection from disease development, including nonalcoholic steatohepatitis (NASH).

Using the genetic material and redacted health records of 540,000 people, encompassing a diverse demographic set, the potential link was discovered. People whose genetic material includes a loss-of-function mutation in a copy of the CIDEB gene are 54% less likely to develop nonalcoholic cirrhosis and 53% less likely to develop nonalcoholic liver diseases such as NASH. In addition to these protections, the mutations granted additional resilience against type 2 diabetes and obesity.

“The unprecedented protective effect that these CIDEB genetic variants have against liver disease provides us with one of our most exciting targets and potential therapeutic approaches for a notoriously hard-to-treat disease where there are currently no approved treatments," Aris Baras, M.D., SVP and head of the Regeneron Genetics Center, said. "RGC has repeatedly demonstrated the value of large-scale genetic sequencing in identifying novel and important targets for many serious diseases and this is yet another example of how we are fueling our pipeline through genetics discovery. Our growing dataset enables us to discover more rare and more powerful protective variants with the ultimate goal of improving human health."

The study was published in the New England Journal of Medicine, revamping an area of medical treatment that has failed to launch thus far. According to the American Liver Foundation, roughly 5% of the adult U.S. population suffers from NASH. Inflammation, liver cell damage and swelling of the liver are all possible manifestations. The condition can develop into cirrhosis after several years. There are no treatments available for conditions under the nonalcoholic fatty liver disease umbrella, including NASH. Several candidates have entered clinical settings without making it to the U.S. Food and Drug Administration (FDA) approval finish line.

Luca Lotta, M.D., Ph.D., vice president and head of cardiometabolic and musculoskeletal disease genetics at Regeneron highlighted the company’s range of liver disease candidates.

"RGC's discovery of CIDEB mutations, with one of the most powerful protections from liver disease seen to date, is a milestone in our understanding of the genetic basis of this disease," he said. "By catalyzing multiple therapeutic development programs targeting distinct genetic mechanisms of liver disease, the RGC's insights are helping Regeneron develop a diversified slate of genetically-validated targets for NASH, including HSD17B13, PNPLA3 and now CIDEB."

This study marks the CIDEB gene as a possible therapeutic target. A treatment that mirrors the effects of the loss-of-function mutation seen in this subset of the population could bring the risk of disease development down significantly.

Regeneron and partner Alnylam have developed an siRNA therapeutic candidate targeting CIDEB that the companies anticipate entering the clinic within the next year. This collaboration has yielded two other investigational gene silencing treatments for NASH, targeting the PNPLA3 and HSD17B13 genes. The latter is already in early clinical studies. All three candidates make use of Alnylam’s RNA interference technology to silence specific genes in the liver.

https://www.biospace.com/article/new-genetic-target-discovered-by-regeneron-could-be-game-changer-for-nash-/