The pain of gout has been with us for millennia at least, but scientists have gone back much further in time – more than 20 million years – to bring back a gene that could help treat the condition and others like it.
When there’s too much uric acid in the blood, it forms crystals in the joints and the kidneys – which then leads to gout and other problems, including kidney disease and liver damage. This overload is known as hyperuricemia.
A gene called uricase could help, by producing an enzyme that helps reduce levels of uric acid. Unfortunately, our human ancestors lost that gene millions of years ago. So, biologists Lais Balico and Eric Gaucher from Georgia State University in the US wondered whether it could be restored.
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“Without uricase, humans are left vulnerable,” says Gaucher. “We wanted to see what would happen if we reactivated the broken gene.”
Evolutionary pressures phased out the uricase gene in several different primate lineages some 20 to 29 million years ago. The thinking is that back then, extra uric acid was beneficial for converting fruit sugar into fat, to help survive food shortages.
That meant it was less advantageous to have uricase, because it limited uric acid. But now that long periods without food aren’t as much of a problem, the uric acid is harming rather than helping the body.
Gaucher and Balico used the CRISPR gene-editing technique to reconstruct the ancient version of the uricase gene, based on the working versions still active in other mammals, and computer models of how the gene may have evolved over time.
They then tested their new gene on engineered human liver cells in the lab, which successfully produced uricase. This had the desired effect, reducing levels of uric acid and the fatty deposits caused by fruit sugar. Similarly positive results were seen in more complex 3D liver spheroids.
“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,” says Gaucher.
This still needs to be demonstrated in animals, but the way that the uricase enzyme found its way into tiny cell compartments called peroxisomes in tests is promising, the team says: it means the uricase is finding its way to the right parts of the cell.
The potential benefits of this kind of treatment go well beyond gout. High uric acid levels have also been linked with different types of cardiovascular disease and high blood pressure, as well as kidney stones.
“Hyperuricemia is a dangerous condition,” says Gaucher. “By lowering uric acid, we could potentially prevent multiple diseases at once.”
However, a lot more research is going to be needed to figure out how to get this uricase gene working safely again in humans – if indeed a tweak like this can be made without interfering with other essential biological processes.
It’s thought that around 1 in 5 people in the US have hyperuricemia, and it can be affected by diet – red meat and alcohol don’t help, for example. While treatments are available, they don’t work for everyone, and sometimes come with unwanted side effects.
“Our genome-editing approach could allow patients to live gout-free lives and potentially prevent fatty liver disease,” says Gaucher.
The research has been published in Scientific Reports.