In February 2025, the parents of KJ Muldoon—a seven-month-old Philadelphia baby born with a severe, neonatal-onset urea cycle disorder (UCD) called CPS1 deficiency—agreed to let doctors treat their son with a new experimental therapy.
Their decision opened the door to one of the most talked-about medical breakthroughs of the year: a first-in-human treatment specifically designed for one person using the CRISPR gene-editing technology. It was delivered “in vivo”— within KJ’s body—to make changes directly in his liver cells.
Doctors continue to monitor KJ closely, but the treatment has been a success so far. It transformed KJ’s severe, neonatal-onset metabolic disorder into a much milder form of the disease. Read the story behind the treatment here and see an update from KJ’s mom below.
Developing that one treatment for one person required teams of researchers from around the globe to work intensely over a period of months at an untold cost. While the revolutionary treatment helped only one baby, it has broadly raised hopes among the entire UCD patient community.
How can more patients benefit from this advance?
Rebecca Ahrens-Nicklas, MD, PhD of the Children’s Hospital of Philadelphia and Kiran Musunuru, MD, PhD, of the University of Pennsylvania’s Perelman School of Medicine were the lead researchers behind KJ’s treatment. They recently shared plans for a new type of clinical trial they hope will help bring such treatments to the broader UCD community and beyond.
This new trial will aim to treat five additional patients with editable variants in any of seven UCD genes, including those that cause CPS1, OTC, ASS1 (citrullinemia), ASA/ASL, ARG1, NAGS, and HHH.
Several related efforts are also underway to make such treatments broadly available for more disorders more quickly, including new federal research funding streams, an accelerated pathway for U.S. Food and Drug Administration (FDA) approvals, and more research teams now working to create similar therapies for other diseases.
Update on Baby KJ
KJ’s mom, Nicole Muldoon, offered insights into their decision to proceed with the treatment and an update on KJ’s progress.
“We wanted KJ to be able to live as normal a life as possible, and thanks to this team, he’s hitting milestones that we get to celebrate together,” she says. “He can catch and throw a ball, loves to play with his siblings, and has just begun walking!”
When a neonatologist first noticed that KJ was experiencing symptoms indicating high ammonia, he was transferred from the Penn Medicine hospital where he was born to the Children’s Hospital of Philadelphia (CHOP).
On a recent podcast, Ahrens-Nicklas credited that neonatologist with being a hero in KJ’s story: “The reason why [KJ] is doing so well today has nothing to do with the gene therapy that we’re going to talk about,” she said. “It’s the fact that when he was about 36 hours old, a really astute neonatologist said something’s wrong with this baby and checked an ammonia.”
Once at CHOP, KJ received emergency treatment to stabilize his condition. For months, he was followed by a metabolic care team and eventually listed for transplant.
During this time, Ahrens-Nicklas and the research team approached the Muldoon family about the customized gene therapy treatment. With the Muldoon’s consent, an international team launched an effort to develop a customized treatment for KJ.
Nicole Muldoon says that the transparency and constant communication with the research team made a big difference in their decision to proceed with the treatment.
“Since individualized gene editing had never been done before, we obviously had a lot of questions about all it entailed, but Rebecca and Kiran [Ahrens-Nicklas and Musunuru] always made sure we were in complete understanding and agreement before each step,” she says.
“It’s made watching KJ’s progress so much more meaningful! Knowing all that he had to go through in the months leading up to his infusions and now seeing him become the playful and curious boy he is has been truly remarkable.”
Researchers look ahead
Ahrens-Nicklas and Musunuru shared their plans to offer treatments like KJ’s to more patients soon in an Oct. 31 commentary in the American Journal of Human Genetics. With funding and support from the National Institutes of Health’s Somatic Cell Genome Editing (SCGE) program, they are continuing development of gene-editing platforms for UCDs as well as for phenylketonuria.
In the commentary, the physicians outlined their thoughts on how to go from a single, personalized gene-editing therapy to a future of interventional genetics, where such treatments could become a standard of care for all UCD patients. They are now working closely with the FDA to rapidly launch the new UCD trial and have published their correspondence with FDA for use by other researchers. It is available through the SCGE website here.
Why did the team choose to develop individualized treatments for urea cycle disorders? In part, because the liver is an excellent target for gene therapy, and because the neonatal-onset forms of the disorders can be so devastating.
But also, the extensive natural history study conducted by the Urea Cycle Disorders Consortium (NUCDF’s research partner) and funded by the NIH’s Rare Diseases Clinical Research Network helped provide the foundational knowledge about the disorders needed by the researchers to develop the treatment and measure its success.
“It is our goal to submit the primary IND for the UCD platform in 2026 with the hope of quickly receiving clearance from the FDA to proceed with a phase I/II umbrella clinical trial,” Ahrens-Nicklas and Musunuru say in the commentary. An IND is an investigational new drug application, which is necessary to move forward with clinical trials in humans.
Other efforts underway
Others in the research community are also working to speed the development and delivery of similar treatments.
FDA leaders Vinay Prasad, MD, MPH and Martin A. Makary, MD, MPH, announced a new regulatory pathway (the “plausible mechanism pathway”) for individualized treatments like KJ’s in a Nov. 12 New England Journal of Medicine article. It offers a new route to market for personalized therapies.
Traditional drug development requires a single drug to be tested through a randomized clinical trial. Such trials would not be feasible for individualized gene editing therapies—they are expensive, slow, and require a large patient population. If instead a platform approach could be adopted, individualized treatments could be developed, tested, and delivered more quickly and easily, reducing costs and saving time.
A platform approach means keeping most of the components needed for treatment development the same and only customizing the specific guide RNA sequence for a patient’s individual genetic mutation. The established “platform” components would not need to be repeatedly tested for safety and efficacy.
“FDA has heard from patients, parents, researchers, clinicians, and developers that current regulations are onerous and unnecessarily demanding, provide unclear patient protection, and stifle innovation. We share this view,” they said. “The FDA will work as a partner and guide in ushering these therapies to market, and our regulatory strategies will evolve to match the pace of scientific advances.”
The federal government has also announced significant new funding to advance similar CRISPR therapies. The Advanced Research Project Agency for Health (ARPA-H), an independent agency within the Department of Health and Human Services, announced two funding opportunities designed to get custom gene editing treatments to more patients:
- The Treating Hereditary Rare Diseases with In Vivo Precision Genetic Medicines (THRIVE) program supports development of pioneering integrated platform technologies for precision genetic medicines
- The Genetic Medicines and Individualized Manufacturing for Everyone (GIVE) program brings state-of-the-art production of treatments closer to the point of care.
And, building on the success of baby KJ’s treatment, other groups are announcing similar research efforts to develop customized treatments for genetic disorders.
For example, the Chan Zuckerberg Initiative and the Innovative Genomics Institute, which was founded in 2015 by Nobel laureate Jennifer Doudna, recently announced the launch of a new Center for Pediatric CRISPR Cures. The new Center will develop treatments for children with severe inborn errors of immunity and severe metabolic disease, with the initial aim of treating eight patients.
Ahrens-Nicklas and Musunuru are hopeful about the future. Their commentary says: “With full-throated support from funding bodies such as the NIH and ARPA-H and from regulatory agencies such as the FDA, we are optimistic that in the coming years, our team and other teams will be able to take tangible steps toward making interventional genetics the standard of care for many diseases.”
Learn more
The Future of Personalized Medicine is Here: KJ’s Story, Children’s Hospital of Philadelphia website. Accessed Nov 18, 2025.
First in human gene editing: a new era for IMD therapies, JIMD Podcasts, Nov. 3, 2025. Features Rebecca Ahrens-Nicklas, Kiran Musunuru and Julien Baruteau, interviewed by host James Nurse.
Ahrens-Nicklas, R. C., & Musunuru, K. (2025). How to create personalized gene editing platforms: Next steps toward interventional genetics. American journal of human genetics, S0002-9297(25)00397-0. Advance online publication. https://doi.org/10.1016/j.ajhg.2025.10.006
Prasad, V., & Makary, M. A. (2025). FDA's New Plausible Mechanism Pathway. The New England journal of medicine, 10.1056/NEJMsb2512695. Advance online publication. https://doi.org/10.1056/NEJMsb2512695
