World's first tailor-made gene editing therapy

KJ can finally live at home with his parents and siblings, after spending the first nine months of his life hospitalized , on a diet and under close observation, due to a serious, incurable and potentially lethal metabolic disease . Everything changed when he became the first patient in the world to experience a new therapy based on personalized gene editing with Crispr technology: between February and April 2025 he underwent three infusions and after a few weeks he already showed some signs of improvement , without serious side effects. The result, which opens up new scenarios for rare genetic diseases , was published in the New England Journal of Medicine by a team from the Children's Hospital of Philadelphia and the University of Pennsylvania.

"This is an important step forward that will allow us to cure diseases that were incurable until now ," says geneticist Giuseppe Novelli of the University of Rome Tor Vergata. " Genetic editing with Crispr is already used clinically on patients with sickle cell anemia and beta-thalassemia , diseases caused by fairly frequent mutations that affect hundreds or thousands of people. In this case, however, we have a personalized approach based on a technological platform that will make editing easier on diseases linked to rarer genetic variants ." Little KJ, who led the way, was born with a rare metabolic disease due to a deficiency in a liver enzyme , carbamoyl phosphate synthase 1 (CPS1) : this condition causes ammonia to accumulate in the blood to toxic levels, with serious consequences for crucial organs such as the brain . "Treating this disease with gene editing seemed very complicated until now for two reasons," observes Novelli. "First, the liver is not easy to reach , unlike other organs such as the eye or blood. Second, its cells proliferate enormously during growth and, if you don't have a highly efficient technique for delivering the correct gene, you risk that it will not be transmitted to all the daughter cells."

The only solution at the moment is to reduce the protein in the diet while waiting for a liver transplant, which however is only accessible to clinically stable patients who are old enough to undergo such a major procedure. And while waiting there is always the risk that hyperammonemia could cause permanent neurological damage or even lead to death. Given KJ's very young age, researchers have tried to help him by developing a therapy based on personalized gene editing , targeting the specific variant of the CPS1 gene identified in the child shortly after birth. Thanks to the experience accumulated over years of preclinical research on similar diseases, the therapy was developed in just six months and was administered via lipid nanoparticles infused in three doses, in February, March and April 2025. In the short time since the treatment, KJ tolerated an increase in dietary protein intake and required fewer drugs against ammonia accumulation. He has also recovered from some common childhood diseases, such as rhinovirus, without ammonia building up in his system. “Although KJ will need to be monitored closely for the rest of his life, our initial results are quite promising ,” says Rebecca Ahrens-Nicklas, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program at Children’s Hospital of Philadelphia and an associate professor of pediatrics at the University of Pennsylvania. “We hope that other researchers will replicate this approach for many rare diseases, giving many patients a real chance at living healthy lives,” adds Kiran Musunuru, a translational medicine expert at the University of Pennsylvania. “The promise of gene therapy that we’ve been hearing about for decades is coming to fruition and will fundamentally transform our approach to medicine .”