Researchers at the Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania are preparing to submit a groundbreaking clinical trial application to the FDA this winter, seeking approval for a novel CRISPR base editing approach that could transform treatment for multiple rare genetic disorders. The initiative follows the remarkable success of baby KJ Muldoon, whose personalized gene editing treatment has become one of the most significant medical stories of 2025.
Revolutionary Treatment Success
When KJ was born prematurely at the University of Pennsylvania last August, he appeared healthy initially but was soon diagnosed with CPS1 deficiency, a rare urea cycle disorder that prevents the liver from breaking down ammonia. The condition can cause permanent brain damage or death as toxic ammonia builds up in the body. KJ was intubated and placed on dialysis, facing the prospect of needing a liver transplant for any chance at a normal life.
Instead of a transplant, KJ received a pioneering gene editing treatment six months later. The therapy, designed specifically for his genetic mutation, involved an infusion of components manufactured just for him and flown to Philadelphia from Iowa, North Dakota, and Canada. The treatment utilized a version of CRISPR called a base editor to fix a single misspelled letter in his DNA.
"This is what we thought we would never get," said Kyle Muldoon, KJ's father, describing a recent moment when his son reacted to an Eagles football game victory. The treatment has not cured KJ but has transformed his severe condition into a much milder form of the disease, eliminating his need for liver transplant.
Scaling Personalized Medicine
The success has generated overwhelming interest from the rare disease community. Since news of KJ's treatment broke in May, the research team has received thousands of pleas from other patients with rare diseases and their families. However, the highly personalized nature of KJ's treatment required massive investments of time, expertise, and capital that aren't easily replicated.
"We need to be able to scale this," said Rebecca Ahrens-Nicklas, the physician who administered KJ's treatment. "In our country, to do that, you have to have an approval so that the drug product can be reimbursed, and we can actually subsidize this to be able to help patients around the country. The technology is there; we just need the infrastructure to evaluate it and deliver it."
Innovative Trial Design
The planned FDA application represents a novel approach to clinical testing. Kiran Musunuru, the geneticist who led development of KJ's treatment, explained that the proposed trial would be open to patients with seven different urea cycle disorders, provided their mutations are amenable to base editing treatment. This "umbrella-of-umbrella" approach would allow individualized treatments to be tested within a single trial framework.
The trial design calls for treating five patients initially, followed by progression to a Phase 3 trial that could enable conditional approval of base editing as a platform technology. "That is absolutely key," Musunuru emphasized. "Not to, you know, say that everything's great after that, there will be many more challenges after that. But if you can't get to that point, this whole thing falls apart, and we won't be able to help all the kids who need help."
Collaborative Scientific Effort
KJ's treatment success resulted from an extensive collaborative effort involving leading researchers across multiple institutions. Ben Kleinstiver at Massachusetts General Hospital and David Liu at the Broad Institute contributed to improving the base editor's ability to make precise DNA modifications. Fyodor Urnov at the Innovative Genomics Institute at the University of California, Berkeley, helped forge a public-private partnership that marshaled resources from Aldevron, IDT, Acuitas Therapeutics, and the Jackson Laboratory.
The treatment has been hailed as a landmark achievement in the five-decade quest to read and repair the genetic code, while also raising important questions about how to safely and equitably scale personalized treatments for rare diseases. The upcoming FDA application represents a critical step toward making this transformative technology accessible to more patients who desperately need it.
