CHOP Treats World’s First Patient to Get Personalized Gene Editing Therapy

Rare Daily Staff

In a medical first, a team at Children’s Hospital of Philadelphia and Penn Medicine has successfully treated a child diagnosed with a rare genetic disorder with customized CRISPR gene editing therapy.

The landmark suggests the possibility of using a bespoke gene editing therapy to treat other people with rare genetic diseases for whom no medical treatments are available.

The child, KJ, was born with a rare metabolic disease known as severe carbamoyl phosphate synthetase 1 (CPS1) deficiency. After spending the first several months of his life in the hospital, on a restrictive diet, KJ received the first dose of his bespoke therapy in February 2025, between six and seven months of age.

The treatment was administered safely, and he is growing well and thriving.

KJ was only days old when he was diagnosed with a rare metabolic disorder and transferred to Children’s Hospital of Philadelphia where doctors were actively researching new cell and gene therapies.

The case is detailed and reported on in a study published by The New England Journal of Medicine and was presented at the American Society of Gene & Cell Therapy Annual Meeting in New Orleans.

“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, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program at Children’s Hospital of Philadelphia and an assistant professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.

While CRISPR-based gene editing can precisely correct disease-causing variants in the human genome, but relatively few diseases benefit from a “one-size-fits-all” gene editing approach because many disease-causing variants exist. It is unlikely that any drug developer would develop a treatment for many of the existing ultra-rare diseases because of the cost and small potential market.

Researchers and clinicians at CHOP and Penn began collaborating to study the feasibility of creating customized gene editing therapies for individual patients in 2023.

Ahrens-Nicklas and Kiran Musunuru, professor for Translational Research in Penn’s Perelman School of Medicine, both co-corresponding authors on the published report, began collaborating to study the feasibility of creating customized gene editing therapies for individual patients in 2023. Both are members of the NIH-funded Somatic Cell Genome Editing Consortium, which supports collaborative genome editing research.

The study was supported by grants from the National Institutes of Health Somatic Cell Genome Editing Program and additional National Institutes of Health grants. Acuitas Therapeutics, Integrated DNA Technologies, Aldevron, and Danaher Corporation made in-kind contributions. The CHOP Research Institute’s Gene Therapy for Inherited Metabolic Disorders Frontier Program provided additional funding.

Ahrens-Nicklas and Musunuru decided to focus on urea cycle disorders. Ammonia is naturally produced during the normal breakdown of proteins in the body. In most cases, the body converts the ammonia to urea and then excretes it through urine. Children with a urea cycle disorder lack an enzyme in the liver needed to convert ammonia to urea. Ammonia then builds up to a toxic level, which can cause organ damage, particularly in the brain and the liver.

Typically, patients with CPS1 deficiency are treated with a liver transplant. However, for patients to receive a liver transplant, they need to be medically stable and old enough to handle such a significant procedure. During that time, episodes of increased ammonia can put patients at risk for ongoing, lifelong neurologic damage or even prove fatal. Because of these threats to lifelong health, the researchers knew that finding new ways to treat patients who are too young and small to receive liver transplants would be life-changing for families whose children faced this disorder.

After years of preclinical research with similar disease-causing variants, Ahrens-Nicklas and Musunuru targeted KJ’s specific variant of CPS1, which was identified soon after his birth. Within six months, their team designed and manufactured a base editing therapy delivered through lipid nanoparticles to the liver to correct KJ’s faulty enzyme.

Kiran Musunru, MD, PhD, MPH, ML, MRA, (left) and Rebecca Ahrens-Nicklas, MD, PhD, (right) led the group of researchers from CHOP and Penn who developed a personalized treatment for baby KJ.

As of April 2025, KJ had received three doses of the therapy with no serious side effects. In the short time since treatment, he has tolerated increased dietary protein and needed less nitrogen scavenger medication. He has also been able to recover from certain typical childhood illnesses like rhinovirus without ammonia building up in his body. Longer follow-up is needed to evaluate the benefits of the therapy fully.

“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.”