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

The infant, KJ, was born with a rare metabolic disease known as severe carbamoyl phosphate synthetase deficiency (CPS1). After spending the first several months of his life in the hospital on a very restrictive diet, KJ received the first dose of his unique therapy in February when he was around six months old.

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

The case was detailed this week in a study published by The New England Journal of Medicine—a landmark finding that could provide a pathway for gene editing technology to be successfully adapted to treat individuals with rare diseases for whom no medical treatments are available.

“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-based gene editing can precisely correct disease-causing variants in the human genome. Such tools are incredibly complex and nuanced, and up to this point, researchers have built them to target more common diseases that affect tens or hundreds of thousands of patients, such as the two diseases which are currently U.S. Food and Drug Administration approved therapies—first sickle cell disease and then beta thalassemia.

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However, relatively few diseases benefit from a “one-size-fits-all” gene editing approach since so many disease-causing variants exist. Even as the field advances, many patients with rare genetic diseases – collectively impacting millions of patients worldwide – have been left behind.

Ahrens-Nicklas and Dr. Kiran Musunuru, a Professor for Translational Research in Penn’s Perelman School of Medicine, who are co-authors of the study, began collaborating to study the feasibility of creating customized gene editing therapies for individual patients in 2023, building upon many years of research into rare metabolic disorders. Both are members of the NIH funded Somatic Cell Genome Editing Consortium, which supports collaborative genome editing research.

The duo decided to focus on urea cycle disorders, which prevent the normal breakdown of proteins in the body, leading to ammonia buildup. Typically, our bodies know to convert the ammonia to urea and then excrete it through urination. However, a child with a urea cycle disorder lacks an enzyme in the liver needed to convert ammonia to urea. It then builds up to a toxic level, which can cause organ damage, particularly in the brain and the liver.

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

In late February, KJ received his first infusion of this experimental therapy and, since then, has received follow-up doses in March and April.

As of last month, KJ had experienced no serious side effects from the three doses. In the short time since treatment, he has tolerated increased dietary protein and needed less nitrogen scavenger medication. He also has been able to recover from certain typical childhood illnesses like rhinovirus without ammonia building up in his body.

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“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.

“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.”

A Future for KJ

Typically, patients with CPS1 deficiency, like KJ, 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 major 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.

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“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’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.

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