Regeneron Genetics Center Discovers Rare Mutations In The CIDEB Gene That Protect Against Liver Disease
New research published in
Regeneron and Alnylam have developed an siRNA therapeutic candidate targeting CIDEB that could enter clinical stages of development in the next year
Unprecedented size of Regeneron Genetics Center human sequence database – representing approximately two million individuals and growing – enables discovery of protective gene variants too rare to be previously identified
"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," said
In the largest sequencing study to date on the genetic basis of liver health, RGC sequenced the exomes of more than 540,000 individuals across five ancestry groups and multiple cohorts, including the
Therapeutics that effectively mimic these protective mutations by blocking CIDEB expression or function could, therefore, potentially help prevent or treat NASH and other forms of liver disease. Based on these findings, Regeneron has already initiated a new therapeutic program to target CIDEB utilizing collaborator Alnylam Pharmaceuticals, Inc.'s RNA interference technology which can effectively silence genes in the liver. Regeneron and Alnylam already have two other investigational gene silencing treatments for NASH identified via human genetics, targeting the PNPLA3 and the HSD17B13 genes. The HSD17B13 program, which is in early-phase human clinical trials, was initiated based on a previous RGC discovery of protective associations for mutations in the HSD17B13 gene.
"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," said
The CIDEB discovery represents the latest example of rare protective gene variants that were identified through the unprecedented size of the RGC large-scale database, that includes genomic data from approximately two million volunteers. Other recently published examples include the discovery of rare gene variants in the GPR75 gene that provide protection against obesity. The CIDEB and GPR75 protective genetics findings suggest that the rarer the genetic discovery, the stronger the effect on disease protection – providing promise for novel therapeutic applications.
About NASH and CIDEB
Nonalcoholic steatohepatitis (NASH) is a severe type of nonalcoholic fatty liver disease (NAFLD), which can lead to cirrhosis, a condition in which liver tissue is replaced by scar tissue, and liver failure. NASH is rapidly becoming the leading cause of liver transplant and poses a substantial unmet medical need; dozens of drug development programs have failed leaving a large treatment gap with no currently approved therapies. In
The CIDEB gene is most highly expressed in human liver cells, where it has been hypothesized to enable fat buildup by helping enlarge fat-storage structures called "lipid droplets" within cells. After discovering the protective association through exome sequencing and health record comparisons, scientists studied the mechanism of the protective CIDEB mutations by silencing the CIDEB gene in human cells to mimic loss of function mutations. They found that this prevented fat buildup in liver cells and resulted in smaller lipid droplets.2,3,4
About the Regeneron Genetics Center
At RGC, scientists around the globe with diverse skills and backgrounds work together to uncover the genetic basis of human disease. Their efforts have culminated in landmark discoveries like CIDEB in NASH and have led to multiple new therapeutic development programs at Regeneron across a range of therapeutic modalities. Since its inception in 2014 and through a network of over 120 collaborators globally, RGC has developed one of the largest and richest human genetics datasets in the world by sequencing around 2 million exomes.
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led for nearly 35 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to nine FDA-approved treatments and product candidates in development, almost all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, pain, hematologic conditions, infectious diseases and rare diseases.
Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite® technologies, such as VelocImmune®, which uses unique genetically humanized mice to produce optimized fully human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world.
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1 Younossi ZM,
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