Scientists suggest ancient gene could offer cure for gout

By Stephen Beech

Gout could be treated by an ancient gene that humans lost millions of years ago, suggests new research.

A form of arthritis caused by crystals that build up in joints and cause swelling and pain, gout is one of humanity’s oldest diseases.

Once regarded as an illness of the wealthy and believed to have been suffered by Henry VIII, the painful condition is the most common form of arthritis in men and affects around one in 40 adults.

Gout has seen a resurgence in recent years with an almost 1,000% rise in cases in just four years in some parts of England.

Symptoms include sudden, severe pain in a joint, often the big toe, as well as hot, swollen, red skin over the affected joint.

Now, scientists at Georgia State University in the United States may have found an ancient solution to treat it.

They 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, including fatty liver disease.

The research team say that the missing piece is uricase, an enzyme most animals still have.

They explained that 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.

But humans and other apes lost the uricase gene around 20 to 29 million years ago.

Some scientists suggest that wasn’t entirely bad at the time.

Researchers, including 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.

But what once helped our ancestors survive now contributes to modern diseases, and that’s what Georgia State Professor Eric Gaucher and his team set out to challenge.

Study co-author Prof. Gaucher said: “Without uricase, humans are left vulnerable.

“We wanted to see what would happen if we reactivated the broken gene.”

Prof. Gaucher and Dr. Lais de Lima Balico 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 researchers found that the results were "dramatic" as uric acid dropped and fructose-driven fat build-up in liver cells was prevented.

But the team said results in isolated cells aren’t always enough, so they pushed the experiment further.

To see if the gene would behave the same way in more complex conditions, the researchers moved from simple liver cells to 3D liver spheroids. The 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.

The researchers said that suggests the therapy could function safely in living systems, not just in isolated cells.

Prof. Gaucher said: “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."

He said the findings, published in the journal Scientific Reports, matter far beyond gout as high uric acid, also called hyperuricemia, is tied to several modern health problems, not just painful joints.

Studies also link it to high blood pressure and cardiovascular disease, among other conditions - with risks that researchers such as Dr. Johnson have compared to high cholesterol, according to research in the journal Hypertension.

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.

Prof. Gaucher said: “Hyperuricemia is a dangerous condition.

“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.

But the researchers say that a CRISPR-based approach could avoid those problems by restoring uricase inside liver cells.

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

He says 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.

Prof. Gaucher says that another option is lipid nanoparticles - the same technology used in some Covid-19 vaccines.

If the approach proves safe, he said it could transform treatment for gout and related metabolic diseases.

But Prof. Gaucher added: “Genome-editing still faces substantial safety concerns.

“Once those are addressed, society will be faced with contentious ethical discussions about who should and should not have access.”