Several research groups are looking for genetic mutations that increase the risk of obesity in the hope of finding new drug targets to control the world’s expanding waistline. However, Regeneron scientists have decided to take the opposite approach. They searched for genetic mutations that would prevent people from gaining excessive weight. And it landed on one gene that the company now wants to target with drugs.
A team at the Regeneron Genetics Center has discovered a mutation in the GPR75 gene that protects against obesity. report In science. Currently, Regeneron drug developers are finding drugs that can mimic the protective properties of the GPR75 variant using their VelocImmune technology, which produces antibodies from humanized mice.
Regeneron researchers began by sequencing about 650,000 exosomes (protein-coding regions of the genome) in the United Kingdom, the United States, and Mexico. People were randomly chosen. That is, researchers did not choose them based on the classification of obesity index or other markers of obesity.
“This allowed us to find genetic variation related to protection against leanness and obesity, in contrast to previous studies that focused primarily on individuals with early-onset severe obesity.” , Said the head of the Doctor of Medicine, Luca Lotta. In an interview with genetics in the therapeutic areas of cardiovascular, metabolism and musculoskeletal at the Regeneron Genetics Center.
The Regeneron team has discovered 16 genes that are strongly associated with BMI. Five of them are particularly interesting because they encode G protein-coupled receptors (GPCRs) expressed in the brain and central nervous system, Lotta explained.
“The brain can control appetite, food preferences, and even the level of physical activity,” Lotta said. “Therefore, the fact that these genes expressed in the brain are associated with body mass index was very interesting.”
Of the five, GPR75 was the most effective in protecting against obesity. In fact, people with at least one inactive copy of GPR75 are 12 pounds lighter and have a 54% lower risk of obesity than those without a genetic abnormality. These protective “loss-of-function mutations” were found in 1 in 3,000 people studied.
To further investigate the role of GPR75 in protection from obesity, researchers fed a high-fat diet to mice designed to lack one or two copies of the gene and mice with two functional copies. Gave it. Normal mice doubled in weight in 14 weeks. Mice with only one functional copy of GPR75 lost 25% of body weight, whereas mice without both copies of the gene lost 44% of body weight. Glucose tolerance tests and insulin sensitivity were also improved in mice designed to lack one or two copies of the gene.
Researchers estimate that about one-third of approved drugs target GPCRs, making them popular targets. However, these products penetrate only about 15% of the GPCR class. This is because it is often difficult to target the receptor with a drug.
Improving its success rate is of great interest among some biopharmaceutical companies. They include Boston-based Tectonic Therapeutics. Release In April, $ 80 million was funded. Tectonic uses a technology platform developed at Harvard University to target GPCRs, which have long been considered non-dragable.
Regeneron explores several different options for targeting obesity genes, including gene silencing drugs, antibodies, and small molecules. Lotta said the effort could take years and would begin with additional preclinical studies aimed at better understanding the genes.
“We need to understand how this pathway works and how it affects appetite, food intake, energy balance and consumption,” Lotta said. “We are very pleased to discover this association and promise to understand if this pathway can be therapeutically altered.”
If Regeneron succeeds in bringing anti-obesity drugs to market, Regeneron will add fuel to its ongoing efforts to increase its presence in metabolic disorders. In February, the company won Approval For Evkeeza, its drug for the treatment of the ultra-rare disease homozygous familial hypercholesterolemia.Now it is working and releasing to expand the market for that drug data Recently from a phase 2 study in severe hypertriglyceridemia.
George Yancopoulos, MD, Ph.D., Co-founder and Chief Scientific Officer of Regeneron. Called the newly discovered variant of GPR75 in the statement a “gene superpower.” By discovering gene mutations that prevent obesity, we can maximize the potential of genetic medicine by instructing where to deploy cutting-edge approaches such as gene editing, gene silencing, and viral vector technology. “I will.”
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