Late last year, dozens of researchers spanning thousands of miles banded together in a race to save one baby boy’s life. The result was a world first: a cutting-edge, gene-editing therapy fashioned for a single person, and produced in a record-breaking six months.
Now, baby KJ Muldoon’s doctors are gearing up to do it all over again, at least five times over. And faster.
The groundbreaking clinical trial, described on 31 October in the American Journal of Human Genetics, will deploy an offshoot of the CRISPR–Cas9 gene-editing technique called base editing, which allows scientists to make precise, single-letter changes to DNA sequences. The study is expected to begin next year, after its organizers spent months negotiating with US regulators over ways to simplify the convoluted path a gene-editing therapy normally has to take before it can enter trials.
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Developing KJ’s treatment was “a pretty hectic and intense six months”, says Kiran Musunuru, a cardiologist at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and one of KJ’s doctors. “But I think we can get it shorter.”
The trial is also the next step towards answering a question that has hung over many families of children with rare diseases since the news broke of KJ’s successful treatment: when will it be our turn? “There is no ‘one size fits all’ in this space,” says Ryan Maple, executive director of the Global Foundation for Peroxisomal Disorders in Tulsa, Oklahoma.
Momentum seems to be building. In addition to the planned clinical trial in Philadelphia, the Center for Pediatric CRISPR Cures, which launched in July at the University of California, Berkeley and the University of California, San Francisco, also aims to develop personalized gene-editing therapies. And in September, the US government’s Advanced Research Projects Agency for Health announced two programmes to fund research into the development and manufacturing of “precision genetic medicine”.
“I’m more optimistic now than I have been in the past,” says Joseph Hacia, a medical geneticist at the Keck School of Medicine at the University of Southern California in Los Angeles.
Therapy for one
In August last year, soon after KJ Muldoon was born, doctors realized that he had a genetic mutation that meant he was unable to produce the normal form of a crucial liver enzyme called carbamoyl phosphate synthetase 1 (CPS1). CPS1 detoxifies ammonia, a natural waste product formed when the body breaks down protein. Ammonia can damage the brain if it is not removed from the bloodstream, and many children with CPS1 deficiency do not live long enough to receive the only known cure: a liver transplant.
But one of KJ’s doctors, Rebecca Ahrens-Nicklas at the Children’s Hospital of Philadelphia in Pennsylvania, had been working with Musunuru to develop a base-editing therapy that could be deployed rapidly to treat children with metabolic disorders. KJ would become their first case.
In late February, KJ received a base-editing therapy designed for him, and him alone. CPS1 deficiency occurs in around one in a million births. The therapy KJ received was designed to find one of the incorrect letters in the DNA sequence of his CPS1 gene and replace it with a different letter that would allow the full CPS1 protein to be produced.
After the therapy, KJ’s ammonia levels dropped, and he was able to reduce his medications. Since then, he’s been hard at work, learning to stand on his own, eating solid foods and working towards taking his first steps. “We celebrate each milestone that KJ accomplishes,” says his mother, Nicole Aaron. “He has a radiance about him that really brightens up every room he enters.”
Expanding access
Musunuru and Ahrens-Nicklas, meanwhile, have been busy working out how to treat more children. Their trial will focus on kids with mutations in one of seven genes, including CPS1, that compromise the ability to process ammonia. They plan to use almost entirely the same base-editing components that were used to treat KJ.
But the researchers will swap out one key component of the base editor: its snippet of guide RNA, which directs the base editor to the DNA letter to be replaced. The sequence of the RNA guide must be tailored to match each child’s specific mutation.
The US Food and Drug Administration (FDA) would normally require each new formulation to undergo a separate clinical trial, with safety tests to ensure that the gene-editing components are not toxic. But in this case, the FDA has indicated that it will accept some of the safety data from KJ’s treatment.
With these changes, Musunuru predicts that the team will be able to shrink the time needed to produce a therapy from six months to three or four.
Guide to regulators
The scientists are also publishing much of the written correspondence they had with the FDA, to serve as a model for other researchers. The team in Pennsylvania will be “a textbook example of a ‘rising tide that lifts all boats’”, says Fyodor Urnov, who studies genome editing at the University of California, Berkeley’s Innovative Genomics Institute (IGI), and helped to create KJ’s treatment. “We at the IGI will gratefully ride on that tide,” he says.
How far that tide can carry everyone is an open question. Musunuru is hopeful that the FDA will consider approving the treatment once another 5 to 15 children have been treated. But the researchers would need to find a company to sponsor the application.
“Personalized treatments are definitely the direction we need to steer towards,” says Maple. “This technology could be more than a game-changer. It could be revolutionary.”
This article is reproduced with permission and was first published on October 31, 2025.
