Â鶹ÒùÔº

Gout, a form of arthritis caused by crystals that build up in joints and cause swelling and pain, is one of humanity's oldest diseases. Scientists at Georgia State University may have found an ancient solution to treat it.

In a published in Scientific Reports, researchers used CRISPR gene editing to bring back a gene that humans lost millions of years ago—and in the process, lowered uric acid levels that cause gout and other conditions.

The missing piece is uricase, an enzyme most animals still have. Uricase breaks down uric acid, the waste product that builds up in blood. When levels climb too high, uric acid forms crystals in the joints and kidneys, leading to painful gout, kidney disease and other health problems.

Humans and other apes lost the uricase gene roughly 20 to 29 million years ago. Some scientists suggest this wasn't entirely bad at the time. Researchers such as Dr. Richard Johnson at the University of Colorado have proposed that higher uric acid levels helped early primates turn fruit sugar into fat, a survival advantage during food shortages, according to a published in Seminars in Nephrology.

Still, what once helped our ancestors survive now contributes to modern diseases, and that's what Eric Gaucher, a biology professor at Georgia State, and his team set out to challenge.

"Without uricase, humans are left vulnerable," said Gaucher, the study's co-author. "We wanted to see what would happen if we reactivated the broken gene."

Working with postdoctoral researcher Lais de Lima Balico, Gaucher used CRISPR-Cas9—a gene-editing tool often called molecular scissors—to put a reconstructed ancient uricase gene into human liver cells so they could see how the enzyme worked.

The results were dramatic: Uric acid dropped and fructose-driven fat buildup in liver cells was prevented. But results in isolated cells aren't always enough, so the team pushed the experiment further.

To see if the gene would behave the same way in more complex conditions, the team moved from simple liver cells to 3D liver spheroids. These miniature lab-grown tissues mimic how organs work in the body. The revived uricase gene lowered uric acid there, too. The enzyme also found its way to peroxisomes—tiny compartments inside cells where uricase normally does its job. That finding suggests the therapy could function safely in living systems, not just in isolated cells.

"By reactivating uricase in human liver cells, we lowered uric acid and stopped the cells from turning excess fructose into triglycerides—the fats that build up in the liver," Gaucher said.

This discovery matters far beyond gout. High uric acid, also called hyperuricemia, is tied to a range of modern health problems, not just painful joints. Studies link it to hypertension and cardiovascular disease, among others—with risks that researchers such as Johnson have compared to high cholesterol, according to published in the journal Hypertension.

Those risks aren't just theoretical. They show up clearly in patient data.

About a quarter to half of patients with high blood pressure also have elevated uric acid, and in new hypertension cases, the overlap jumps to 90%, according to the study.

"Hyperuricemia is a dangerous condition," Gaucher said. "By lowering uric acid, we could potentially prevent multiple diseases at once."

Current gout treatments don't work for everyone, and some patients react badly to lab-made uricase therapies. A CRISPR-based approach could sidestep those problems by restoring uricase inside liver cells.

"Our genome-editing approach could allow patients to live gout-free lives and potentially prevent fatty liver disease," Gaucher said.

Next come animal studies and, if results hold, human trials. Potential delivery options range from direct injections to returning lab-modified liver cells to patients. Another option is lipid nanoparticles—the same technology used in some COVID-19 vaccines.

If the approach proves safe, Gaucher said it could transform treatment for gout and related metabolic diseases. But hurdles remain.

"Genome-editing still faces substantial safety concerns," he said. "Once those are addressed, society will be faced with contentious ethical discussions about who should and should not have access."