An infant with a rare metabolic disease became the world’s first patient to be treated with a personalized CRISPR gene-editing treatment in a landmark study between Penn Medicine and the Children’s Hospital of Philadelphia.
At one week old, KJ Muldoon was diagnosed with CPS1 deficiency, which results in approximately half of the infants with the disorder dying within the first week of life. Then, KJ received the first-ever custom gene-editing infusion at six months old and began to improve.
CPS1 is a rare disorder affecting just one in 1.3 million babies, which is caused by a mutation that prevents the body from ridding itself of ammonia. KJ was initially given just six months to live, and his doctors predicted that he would have severe mental and developmental delays, eventually needing a liver transplant.
The gene therapy was designed to fix his precise mutation, and within weeks, the boy — who had lived in the hospital full-time since birth — started reaching critical developmental milestones for his age.
“I don’t think I’m exaggerating when I say that this is the future of medicine,” Dr. Kiran Musunuru, a translational research professor at Penn Med, said. “This is the first step towards the use of gene-editing therapies to treat a wide variety of rare genetic disorders for which there are actually very few treatments currently in development at all.”
Rebecca Ahrens-Nicklas — co-author of the study, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program at CHOP, and assistant professor of Pediatrics in the Perelman School of Medicine — and Musunuru presented their work at the American Society of Gene & Cell Therapy Annual Meeting last week.
Ahrens-Nicklas and Musunuru have been developing treatments for the kind of liver-targeting condition KJ suffers from since 2023, which allowed them to rapidly create a base-editing therapy — a form of CRISPR technology — that corrects one of KJ’s two copies of the CPS1 gene.
Illnesses such as CPS1 deficiency are caused by one incorrect DNA letter among the three billion in the human genome. To correct this error, the information instructing the cell to edit the gene and CRISPR technology that finds the incorrect DNA letter is protected while traveling to the liver, where the edit to the DNA sequence is made.
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Ahrens-Nicklas explained that this process makes KJ’s treatment unique to him.
“The drug is really designed only for KJ, so the genetic variants that he has are specific to him,” he said. “It's personalized medicine.”
The method used to design KJ’s treatment can be replicated to fix mutations in other locations within other people’s DNA, as only the CRISPR instructions that lead the editor to the mutated site would need to be changed. As a result, pharmaceutical companies would not have to go through Food and Drug Administration approval for each personalized cure, allowing them to treat more patients.
This could help standardize treatments for more common genetic disorders such as sickle cell disease, cystic fibrosis, Huntington’s disease, and muscular dystrophy, according to former FDA official Peter Marks. More than 30 million people in the United States currently have one of over 7,000 rare genetic diseases that require various gene-editing treatments.
Harvard University professor David Liu, whose lab invented the gene-editing method used to fix KJ’s mutation, said the speed at which his treatment was developed was “astounding.”
“These steps traditionally take the better part of a decade, if not longer,” Liu said. KJ’s treatment took only approximately six months to develop.
Due to the urgency of KJ’s case, the research team contacted U.S. regulators early on. The FDA approved their application within “just one week,” recognizing the “unusual circumstance” and deviating from “business as usual.”
Marks explained that the treatment is “one of the most potentially transformational technologies out there” and said it could “really transform health care.”
Fyoder Urnov — a professor at the University of California, Berkeley and part of KJ’s treatment team — emphasized the team’s pride after KJ’s survival.
“I don’t think this could have happened in any country other than the U.S.,” Urnov said. “This is the most significant thing we have ever done.”
