In a groundbreaking achievement, doctors at Children’s Hospital of Philadelphia and Penn Medicine have successfully used a tailored CRISPR gene editing therapy to treat a young child, KJ, suffering from a rare genetic condition.

KJ was diagnosed with severe carbamoyl phosphate synthetase deficiency (CPS1), a rare metabolic disorder. he received his first dose of the personalized therapy in February, at approximately six months old, after spending his early months in the hospital on a highly restricted diet.

The treatment was administered without complications, and KJ is currently thriving.

The details of this case were published this week in a study in the New England Journal of Medicine, marking a significant step forward. The findings suggest a potential route for adapting gene editing technology to treat individuals with rare diseases who currently lack effective medical options.

“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 Dr. Rebecca Ahrens-Nicklas, director of the Gene Therapy for Inherited Metabolic Disorders Frontier program at the Hospital and an assistant professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.

CRISPR gene editing allows for precise correction of disease-causing genetic variations. These tools are complex, and until now, they have primarily targeted more common diseases affecting large patient populations, such as sickle cell disease and beta thalassemia, both of which have FDA-approved therapies.

However, due to the vast number of disease-causing variants, a universal gene editing approach is not suitable for many diseases. As the field progresses, many individuals with rare genetic diseases, which collectively affect millions globally, have been excluded.

Dr. ahrens-Nicklas and Dr. Kiran Musunuru,a Professor for Translational Research in Penn’s Perelman School of Medicine,began collaborating in 2023 to explore the possibility of creating customized gene editing therapies for individual patients,building on years of research into rare metabolic disorders. Both are part of the NIH-funded Somatic Cell Genome Editing Consortium, which supports collaborative genome editing research.

Their focus shifted to urea cycle disorders, which disrupt the normal breakdown of proteins, leading to a buildup of ammonia. Typically, the body converts ammonia to urea, which is then excreted through urination. However,children with urea cycle disorders lack a necessary liver enzyme to complete this conversion,causing ammonia to accumulate to toxic levels,potentially damaging organs,especially the brain and liver.

Following extensive preclinical research on 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 the liver, to correct KJ’s defective enzyme.

KJ received his initial infusion of this experimental therapy in late February, followed by subsequent doses in March and April.

As of last month, KJ has shown no significant side effects from the treatments. Since starting the therapy, he has been able to tolerate increased dietary protein and requires less nitrogen scavenger medication. He has also recovered from common childhood illnesses, such as rhinovirus, without experiencing ammonia buildup.

“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.”

“While KJ will need to be monitored carefully for the rest of his life,our initial findings are quite promising,” said Ahrens-Nicklas in a hospital press release.

“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 investigators will replicate this method for many rare diseases and give many patients a fair shot at living a healthy life,” Musunuru said.

A Future for KJ

the standard treatment for CPS1 deficiency is a liver transplant. Though, patients must be medically stable and old enough to undergo this major surgery. During the waiting period, episodes of high ammonia levels can cause permanent neurological damage or be fatal. Recognizing these risks, the researchers sought new treatments for young patients who are not yet eligible for liver transplants, aiming to improve outcomes for affected families.

“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 obligation 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’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,” said his father, Kyle Muldoon.