CHOP and Penn Medicine Deliver First Personalized CRISPR Gene Therapy to Infant with Rare Genetic Disorder

In a historic advancement in medicine, doctors at Children's Hospital of Philadelphia (CHOP) and Penn Medicine have successfully treated a young patient using a custom CRISPR gene editing therapy. The patient, an infant named KJ, was born with a rare metabolic condition called severe carbamoyl phosphate synthetase 1 (CPS1) deficiency. After spending the early months of his life in the hospital and following a very restricted diet, KJ received his first dose of the personalized therapy in February 2025, when he was about six to seven months old. The treatment was administered without complications, and he is now showing healthy growth and development.

This case is outlined in a study published today in The New England Journal of Medicine and was also shared at the American Society of Gene & Cell Therapy Annual Meeting in New Orleans. This breakthrough could open new possibilities for using gene editing to help patients with rare conditions that currently have no available treatments.

"Years and years of progress in gene editing and collaboration between researchers and clinicians made this moment possible, and while KJ is just one patient, we hope he is the first of many to benefit from a methodology that can be scaled to fit an individual patient's needs," said Rebecca Ahrens-Nicklas, MD, PhD, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program (GTIMD) at Children's Hospital of Philadelphia and an assistant professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.

CRISPR (clustered regularly interspaced short palindromic repeats) gene editing allows for precise correction of mutations in the human genome. Until now, these tools have largely focused on more widespread conditions affecting large patient populations, such as the two currently FDA-approved CRISPR therapies for sickle cell disease and beta thalassemia. However, since rare diseases often result from a wide array of genetic variants, a single, uniform approach does not apply. This leaves many individuals with rare conditions without access to these cutting-edge treatments.

Ahrens-Nicklas and Kiran Musunuru, MD, PhD, the Barry J. Gertz Professor for Translational Research in Penn’s Perelman School of Medicine and co-corresponding author of the study, began collaborating in 2023 to explore personalized gene editing solutions for individual patients. Their work builds on extensive prior research into rare metabolic diseases and the technical feasibility of gene editing. Both researchers are part of the NIH-funded Somatic Cell Genome Editing Consortium, which supports collaborative research in this area.

The team chose to focus on urea cycle disorders, a group of conditions in which the body cannot properly process ammonia, a byproduct of protein digestion. Normally, the body converts ammonia to urea for excretion, but in these disorders, the liver lacks an essential enzyme. This causes toxic ammonia buildup, which can damage organs such as the brain and liver.

After identifying KJ’s specific CPS1 mutation shortly after his birth, the team spent six months developing a base editing therapy that could be delivered to the liver via lipid nanoparticles. The therapy was designed to correct the faulty enzyme causing the disorder. KJ received the initial dose in February 2025, followed by additional doses in March and April. The published study describes the design and expedited development of the therapy, accomplished with academic and industry collaboration.

By April 2025, KJ had completed three rounds of therapy with no major side effects. Since starting treatment, he has shown progress by tolerating more protein in his diet and requiring less medication to manage nitrogen levels. He has also weathered typical childhood illnesses, like rhinovirus, without experiencing dangerous ammonia spikes. Ongoing monitoring will be needed to assess the therapy’s long-term effects.

"While KJ will need to be monitored carefully for the rest of his life, our initial findings are quite promising," Ahrens-Nicklas said.

"We want each and every patient to have the potential to experience the same results we saw in this first patient, and we hope that other academic investigators will replicate this method for many rare diseases and give many patients a fair shot at living a healthy life," Musunuru said. "The promise of gene therapy that we've heard about for decades is coming to fruition, and it's going to utterly transform the way we approach medicine."

In typical cases, children with CPS1 deficiency undergo liver transplants. However, they must be stable and of a sufficient age for the surgery. In the meantime, they are at constant risk from high ammonia levels, which can cause permanent neurological damage or even be fatal. This made it urgent for the research team to explore other treatment paths for very young patients like KJ.

"We would do anything for our kids, so with KJ, we wanted to figure out how we were going to support him and how we were going to get him to the point where he can do all the things a normal kid should be able to do," his mother, Nicole Muldoon, said. "We thought it was our responsibility to help our child, so when the doctors came to us with their idea, we put our trust in them in the hopes that it could help not just KJ but other families in our position."

"We've been in the thick of this since KJ was born, and our whole world's been revolving around this little guy and his stay in the hospital," his father, Kyle Muldoon, said. "We're so excited to be able to finally be together at home so that KJ can be with his siblings, and we can finally take a deep breath."