AstraZeneca and Regeneron Partner to Develop GPR75-Targeted Small Molecule Therapy Mimicking Rare Anti-Obesity Genetic Mutation

On July 27, 2021, AstraZeneca announced a collaboration with Regeneron to co-develop and commercialize novel small-molecule drugs targeting GPR75 for the treatment of obesity and related comorbidities.

In a research paper recently published in the top academic journal *Science*, researchers conducted exome sequencing on nearly 650,000 individuals and ultimately identified 16 rare genetic mutations that affect body mass index (BMI). Among these, individuals carrying at least one inactive copy of *GPR75* weighed an average of 5.3 kg less and had a 54% lower risk of obesity compared to those without the mutation.

Researchers further investigated the effect of the GPR75 gene on body weight in mice. They knocked out this gene to simulate a loss of protein function. As a result, despite being fed the same high-fat diet daily, the mutant mice maintained normal blood glucose control, and their weight gain was significantly lower than that of wild-type mice.

▲ Mutant mice with one allele knocked out and those with both alleles knocked out exhibited 25% and 44% lower weight gain, respectively, compared to wild-type mice. (Image source: Reference [4])

Glycemic control was also significantly improved in GPR75-knockout mice. Therefore, inhibition of GPR75 may provide a novel therapeutic strategy for obesity.

Note: The original text has been abridged.

References:

[1] AstraZeneca and Regeneron to research, develop and commercialise new small molecule medicines for obesity. Retrieved July 27, 2021, from https://www.astrazeneca.com/media-centre/press-releases/2021/astrazeneca-and-regeneron-to-research-develop-and-commercialise-new-small-molecule-medicines-for-obesity.html

[2] Regeneron's latest genetics discovery hooks AstraZeneca — now all-in on developing small molecules for obesity. Retrieved July 27, 2021, from https://endpts.com/regenerons-latest-genetics-discovery-hooks-astrazeneca-now-all-in-on-developing-small-molecules-for-obesity/

[3] AstraZeneca teams up with Regeneron for obesity-busting drug pact focused on genetics. Retrieved July 27, 2021, from https://www.fiercebiotech.com/biotech/astrazeneca-teams-up-regeneron-for-obesity-busting-drug-pact-focused-genetics

[4] Parsa Akbari et al., (2021) Sequencingof 640,000 exomes identifies GPR75 variants associated with protection fromobesity. Science DOI: 10.1126/science.abf8683

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