An NIH-supported research team has achieved a groundbreaking medical milestone by developing and safely delivering a personalized gene editing therapy to treat an infant diagnosed shortly after birth with carbamoyl phosphate synthetase 1 (CPS1) deficiency, a rare and life-threatening genetic disorder. This marks the first time that this specific CRISPR-based gene editing technology has been successfully used to treat a human patient.

The therapy was created by researchers at the Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania (Penn). Using the advanced gene-editing platform CRISPR, which enables precise DNA modifications inside living cells, the team designed a treatment to correct the specific gene mutation in the infant’s liver cells responsible for CPS1 deficiency. Importantly, this personalized CRISPR therapy targeted only non-reproductive cells, ensuring genetic changes affected only the patient and not future generations.

CPS1 deficiency impairs the body’s ability to break down toxic byproducts from protein metabolism in the liver, causing dangerous ammonia accumulation that can severely damage the brain and liver. The standard treatment involves a low-protein diet until a liver transplant can be performed, but the waiting period carries risks of rapid organ failure triggered by infections or other stressors. High ammonia levels can lead to coma, brain swelling, permanent brain damage, or death.

From diagnosis to treatment, the process took just six months. The infant, known as KJ, received an initial low dose of the gene therapy at six months old, followed by a higher dose later. Signs of treatment effectiveness appeared quickly, including the child’s improved ability to tolerate increased dietary protein and a reduced need for medications to control ammonia levels. Remarkably, when KJ contracted a cold and later a gastrointestinal illness-normally dangerous for CPS1 patients-he recovered without severe complications, indicating a significant improvement in his condition.

The gene editing platform used in this therapy is built on reusable components allowing rapid customization, which researchers believe can be adapted to treat a broad spectrum of rare genetic diseases.

While the researchers remain cautiously optimistic, they highlight this success as a promising step toward scalable, personalized gene therapies for patients with rare diseases lacking effective treatments. The findings were presented at the American Society of Gene & Cell Therapy Meeting on May 15, 2025, and detailed in The New England Journal of Medicine.

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