Reviving a Gene to Tackle Gout
Gout, a condition that has plagued humans for thousands of years, is now the focus of research aiming to combat not just this painful ailment but others as well. Scientists have delved much deeper into history—over 20 million years back—to bring back a gene that could potentially aid treatment.
The root of gout lies in high levels of uric acid in the bloodstream. When too much uric acid accumulates, it crystallizes in the joints and kidneys, leading to not only gout but also serious issues like kidney disease and liver damage, a condition referred to as hyperuricemia.
One potential solution is a gene called uricase, which creates an enzyme that helps regulate uric acid levels. However, early humans lost this gene millions of years ago. This prompted biologists Lais Balico and Eric Gaucher from Georgia State University to consider whether it could be revived.
“Humans became vulnerable without uricase,” says Gaucher. “We were curious about reactivating the broken gene.” Interestingly, evolutionary pressures led to the loss of uricase in various primate lineages between 20 and 29 million years ago. At that time, excess uric acid might have been advantageous for converting fruit sugars into fat to survive periods of food scarcity.
The situation’s different now; long fasting periods aren’t common, and elevated uric acid can actually harm the body.
Gaucher and Balico employed CRISPR gene-editing technology to recreate the ancient uricase gene, using active versions found in other mammals and computer simulations of its evolution.
In laboratory tests, the newly engineered gene successfully produced uricase in human liver cells, effectively lowering uric acid levels and preventing the conversion of excess fructose into triglycerides—fats that accumulate in the liver. Encouragingly, similar outcomes were observed in sophisticated 3D liver spheroid models.
“Activating uricase in human liver cells helped us decrease uric acid and halted the buildup of triglycerides,” Gaucher notes.
While animal testing is still needed, initial results seem promising, especially since the uricase enzyme appears to be localized correctly within cell compartments known as peroxisomes.
These findings might have broader implications. Elevated uric acid levels are also tied to various cardiovascular diseases and conditions like high blood pressure and kidney stones.
“Hyperuricemia can be quite dangerous,” says Gaucher. “Reducing uric acid levels could help prevent numerous diseases simultaneously.”
That said, more research is necessary to ensure that this revamped uricase gene can be implemented safely in humans without disrupting other vital biological functions.
About one in five people in the US experience hyperuricemia, and factors like diet—particularly red meat and alcohol—can exacerbate the condition. Current treatments vary in efficacy and sometimes have unwanted side effects.
“Our genome-editing technique might enable patients to lead gout-free lives and possibly avoid fatty liver disease,” Gaucher reflects.
The research findings have been shared in Scientific Reports.
