Researchers at Georgia State University have used CRISPR gene-editing to restore an ancient enzyme called uricase in human liver cells, significantly lowering uric acid levels and halting fat accumulation. This breakthrough, detailed in Scientific Reports, targets gout and related metabolic diseases stemming from humans' loss of the gene millions of years ago. The findings suggest potential new therapies for conditions like hypertension and cardiovascular disease.
Gout, one of the oldest documented human illnesses, arises when uric acid crystals form in joints, causing severe pain and swelling as a form of arthritis. Humans and other apes lost the uricase gene, which breaks down uric acid, roughly 20 to 29 million years ago. Some research, including work by Dr. Richard Johnson of the University of Colorado cited in Seminars in Nephrology, posits that elevated uric acid once aided early primates in converting fruit sugars to fat for survival during scarcity.
In a study published in Scientific Reports, Georgia State University biology professor Eric Gaucher and postdoctoral researcher Lais de Lima Balico used CRISPR-Cas9 to insert a reconstructed version of the ancient uricase gene into human liver cells. The enzyme reduced uric acid levels sharply and prevented liver cells from accumulating fat when exposed to fructose. Further tests in 3D liver spheroids, which mimic organ function, showed the uricase entering peroxisomes, the natural site for its activity, indicating potential safety in organisms.
"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. High uric acid, or hyperuricemia, links to broader issues: studies in Hypertension journal associate it with hypertension and cardiovascular risks comparable to high cholesterol. Between 25% and 50% of people with high blood pressure have elevated uric acid, rising to 90% in newly diagnosed cases.
"Hyperuricemia is a dangerous condition," Gaucher added. "By lowering uric acid, we could potentially prevent multiple diseases at once." Current gout treatments fail some patients or cause reactions to uricase drugs. The CRISPR approach might enable gout-free lives and prevent fatty liver disease via methods like injections or lipid nanoparticles, as in some COVID-19 vaccines.
Next steps include animal studies and human trials, pending safety resolutions. Gaucher noted ethical challenges ahead: "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."