The genes SIM1 and MC4R regulate food intake by signaling the feeling of being full, which is why mutations in those genes are associated with severe obesity. Even if just one of the two copies of those genes that a person inherits from both parents is bad, he or she will most likely feel hungry all the time.
What if the one working copy of a satiety-promoting gene could be turbocharged in some way to make up for the lack of functionality of the mutated copy? Scientists at the University of California, San Francisco, went looking for an answer to that question and found it in CRISPR—the gene-editing technology that has garnered attention for its potential use in editing out genes that cause inherited diseases.
But instead of using CRISPR to cut out the bad obesity genes, the UCSF team modified the technology so it could amplify the activity of the good copies. The technology they developed, dubbed CRISPRa (for activation), finds the working satiety gene and then turns up its volume. When the CRISPRa was delivered to the brains of mice with only one working copy of either SIM1 or MC4R it prevented them from becoming obese, the researchers reported in the journal Science.
The team monitored two groups of genetically engineered mice for 10 months—some that had one injection of the CRISPRa treatment and some that did not. The treated mice weighed up to 40% less than the untreated animals, they discovered. Both groups were fed a normal diet, but the untreated mice couldn’t stop eating, said lead author Navneet Matharu, Ph.D., a researcher at UCSF, in a statement. By the time they were 10 weeks old they were already severely obese, she said.
One of the concerns about CRISPR is that editing genes could cause dangerous off-target effects, but the UCSF researchers believe that using the technology to activate genes could prevent that problem. That’s because CRISPRa doesn’t permanently change the genome, they noted. Instead it targets noncoding DNA sequences that merely turn genes on and off.
Finding a gene-focused cure for obesity is a popular pursuit. Most recently, a team at Flinders University in South Australia reported that when they removed the gene RCAN1 from mice and gave them a high-fat diet, they did not gain weight. They believe that removing RCAN1 helps the body transform unhealthy white fat into calorie-burning brown fat. Researchers at the University of Pennsylvania are working on achieving a similar effect by inhibiting the gene FLCN.
UCSF’s Matharu believes gene amplification with CRISPR holds promise for treating more than just obesity. For example, some diseases are caused by "microdeletions," or the loss of large segments of chromosomes. Conventional CRISPR can’t address those diseases, but CRISPRa might help compensate for those losses.
"These results demonstrate that CRISPRa can be used to up the dosage of genes in diseases that result from a missing copy, providing a potential cure for certain forms of obesity as well as hundreds of other diseases," Matharu said.