Several research groups have hunted for gene mutations that confer an increased risk of obesity in the hopes of finding new drug targets to curb the world’s expanding waistline. But scientists at Regeneron decided to take the opposite approach: They looked for genetic variants that keep people from gaining excessive amounts of weight—and they landed on one gene the company is now hoping to target with drugs.
A team at Regeneron Genetics Center has discovered mutations in the gene GPR75 that protect against obesity, they reported in Science. Now, drug developers at Regeneron are using the company’s VelocImmune technology, which generates antibodies from humanized mice, to find drugs that can mimic the protective properties of the GPR75 variants.
Regeneron’s researchers started by sequencing the exomes—the protein-coding regions of genomes—from nearly 650,000 people in the U.K., U.S. and Mexico. The people were selected at random, meaning the researchers didn’t choose them based on their body mass index or any other marker of obesity.
“That allowed us to find genetic variants associated with leanness and protection against obesity, in contrast with previous research, which focused mostly on individuals who developed early-onset, severe obesity,” said Luca Lotta, M.D., Ph.D., head of cardiovascular, metabolic and musculoskeletal therapeutic area genetics at Regeneron Genetics Center, in an interview.
The Regeneron team found 16 genes strongly associated with BMI. Five of those are particularly interesting, because they encode G protein-coupled receptors (GPCRs) that are expressed in the brain and central nervous system, Lotta explained.
“The brain can control appetite, food preferences, even the level of physical activity,” Lotta said. “So the fact that these brain-expressed genes were associated with body mass index was of great interest.”
Of the five, GPR75 had the greatest effect on protection against obesity. In fact, people with at least one inactive copy of GPR75 were 12 pounds lighter and faced a 54% lower risk of obesity than did people without the gene abnormality. These protective “loss-of-function mutations” were found in one out of every 3,000 people studied.
To further probe GPR75's role in protecting against obesity, the researchers fed a high-fat diet to mice that were engineered to lack either one or two copies of the gene as well as to mice with two functioning copies. The normal mice doubled their weight in 14 weeks. Mice with just one functioning copy of GPR75 gained 25% less body weight, while those that lacked both copies of the gene gained 44% less. Glucose tolerance and insulin sensitivity also improved in mice engineered to lack either one or two copies of the gene.
Researchers have estimated that about a third of approved drugs target GPCRs, making them a popular target. But those products only penetrate about 15% of the GPCR class, because the receptors are often difficult to target with drugs.
Improving that success rate is of high interest among some biopharma companies. They include Boston-based Tectonic Therapeutics, which launched with $80 million in funding in April. Tectonic is using a technology platform developed at Harvard University to target GPCRs that have long been thought to be undruggable.
Regeneron will investigate several different alternatives for targeting the gene in obesity, including gene-silencing drugs, antibodies and small molecules. Lotta said the effort could take several years and will start with additional preclinical work aimed at better understanding the gene.
“We need to understand how this pathway works, what its impact is on appetite, food intake, and energy balance and expenditure,” Lotta said. “We’re incredibly excited to have found this association, and we’re committed to understanding if this pathway can be modified therapeutically.”
If Regeneron succeeds in bringing an anti-obesity drug to market, it will add fuel to its ongoing effort boost its presence in metabolic diseases. In February, the company won approval for Evkeeza, its drug to treat the ultra-rare disease homozygous familial hypercholesterolemia. Now, it’s working to expand the market for that drug, releasing data recently from a phase 2 trial in severe hypertriglyceridemia.
George Yancopoulos, M.D., Ph.D., Regeneron’s co-founder and chief scientific officer, called the newly discovered GPR75 variants “genetic superpowers” in a statement. The discovery of gene mutations that protect against obesity, he said, “will allow us to unlock the full potential of genetic medicine by instructing on where to deploy cutting-edge approaches like gene-editing, gene-silencing and viral vector technologies.”