In a historic medical breakthrough, an infant with a rare genetic disorder has been successfully treated with a custom-designed CRISPR gene-editing therapy by a team from Children’s Hospital of Philadelphia (CHOP) and Penn Medicine. Infant KJ was born with a rare metabolic disorder called carbamoylphosphate synthetase 1 deficiency (CPS1 deficiency). After spending the first few months of life in the hospital on a highly restrictive diet, KJ received the first dose of his custom-designed therapy in February 2025, between six and seven months of age. The treatment was safe, and he is growing and thriving.
The case was detailed today in a study in the New England Journal of Medicine and presented at the annual meeting of the American Society of Gene & Cell Therapy in New Orleans. This groundbreaking discovery could pave the way for the successful use of genome-editing technology to treat people with rare diseases for whom there is no medical treatment.
Credits
Children's Hospital of Philadelphia
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-based gene editing can precisely correct disease-causing variants in the human genome. Gene-editing tools are incredibly complex and nuanced, and researchers have so far developed them to address more common diseases that affect tens or hundreds of thousands of patients, such as the two diseases for which there are currently U.S. Food and Drug Administration-approved therapies: sickle cell disease and beta-thalassemia. However, because there are so many disease-causing variants, relatively few diseases benefit from a one-size-fits-all approach to gene editing. Despite advances in the field, many patients with rare genetic diseases—millions of patients worldwide in total—remain unaddressed.
Ahrens-Nicklas and Musunuru focused on urea cycle disorders. In the normal breakdown of protein in the body, ammonia is naturally produced. Normally, our bodies convert ammonia into urea and then excrete it through urine. However, children with a urea cycle disorder lack an enzyme in the liver that is needed to convert ammonia into urea. This causes ammonia to build up to toxic levels, which can cause organ damage, particularly in the brain and liver.
After years of preclinical research with similar disease-causing variants, Ahrens-Nicklas and Musunuru targeted KJ's specific CPS1 variant, identified shortly after his birth. Within six months, their team developed and produced a base editing therapy delivered via lipid nanoparticles to correct KJ's faulty enzyme. In late February 2025, KJ received the first infusion of this experimental therapy, and he has since received additional doses in March and April 2025. In the recent publication in the New England Journal of Medicine, the researchers, along with their academic and industry partners, describe the custom CRISPR gene editing therapy that was developed with great care, yet rapidly, for KJ's treatment.
By April 2025, KJ had received three doses of the therapy without any serious side effects. In the short time since treatment, he is tolerating an increased protein intake and requires less nitrogen-scavenging medication. He has also been able to recover from common childhood illnesses, such as rhinovirus, without accumulating ammonia in his body. Longer follow-up studies are needed to fully assess the therapy's benefit.
"Although KJ will require careful monitoring for the rest of his life, our initial results are quite promising," said Ahrens-Nicklas.
Journal
New England Journal of Medicine
DOI
