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Infant with rare disease receives world’s first personalized gene-editing therapy

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13 Min Read

Sara Kellner , 2025-05-16 16:07:00

Key takeaways:

  • An infant with a rare urea cycle disorder became the first patient to receive a personalized gene-editing therapy.
  • His care team developed the one-of-a-kind medication in just 6 months.

By the second day of his life, Kyle and Nicole Muldoon knew their newborn son was very sick.

During a routine exam in the NICU, his doctor noticed his arm was shaking down slowly after being lifted, rather than falling like a typical baby. Then, his labs showed extremely high levels of ammonia in his blood, indicating that he had a urea cycle disorder.



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Kyle and Nicole said the following weeks were a “crash course” in urea cycle deficiencies and their son’s specific condition: carbamoyl phosphate synthetase 1 (CPS1) deficiency.

The infant’s doctor explained that CPS1 deficiency is “an incredibly severe, ultra rare disease” in which the liver lacks an enzyme needed to convert ammonia to urea and excrete it through urination.

“The ammonia buildup can be life-threatening shortly after birth,” Rebecca C. Ahrens-Nicklas, MD, PhD, a physician-scientist and director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program at The Children’s Hospital of Philadelphia, told reporters during a press conference this week. “[He] was lucky that a thoughtful doctor identified that he had signs of an elevated ammonia level, including poor feeding and sleepiness.”

Ahrens-Nicklas said the Muldoons’ son immediately started dialysis treatments to remove the ammonia from his body, and the original plan was to wait until he grew large enough for a liver transplant, which is the usual treatment for his condition.

Later, he transitioned from dialysis to a long-term treatment including glycerol phenylbutyrate, a nitrogen-scavenger drug, and citrulline supplementation. He consumed a low-protein diet.

Ahrens-Nicklas said CPS1 deficiency is the most severe form of urea cycle disorder, and more than 50% of babies with the defect will die during the neonatal period.

“I knew he was going to have a very challenging path, even with excellent care,” she said.

So, she pitched the idea for a gene-editing treatment that had never been done before.

“Nicole is very analytical … and I am a gut guy,” Kyle Muldoon said during the press conference. “When we had met with Dr. Ahrens-Nicklas, I had a very profound feeling about this gene editing, which was such a foreign concept.”

“To Dr. Ahrens’ credit, she was so humble in the way she was telling us about this extraordinary thing that was essentially going to possibly save and enhance our child’s life,” he said. “We prayed, we talked to people, we gathered information, and we eventually decided that this was the way we were going to go.”

Which is how their son became the world’s first recipient of a personalized gene-editing therapy in what has been hailed as a medical milestone.

One-of-a-kind therapy

Ahrens-Nicklas teamed up with Kiran Musunuru, MD, PhD, a cardiologist and Barry J. Gertz Professor for Translational Research at the University of Pennsylvania Perelman School of Medicine, to investigate gene-editing therapies 4 years ago. Musunuru said he has been working for more than a decade on gene-editing treatment for high cholesterol.

“We can do this by changing the spelling of a cholesterol gene, switching one letter to another letter so it is turned off,” he explained during the press conference. “We have developed a treatment that can be given to a patient through an IV infusion. It goes straight to the liver, and it turns off the cholesterol gene in the liver, and this treatment is showing great success in clinical trials.”

Ahrens-Nicklas originally began collaborating with Musunuru in 2021 to develop treatments for phenylketonuria (PKU). Similar to the cholesterol treatments his lab was working on already, the PKU treatments involved correcting misspellings — or mutations — in genes to make the liver create enzymes that it was not previously creating.

“A little more than 2 years ago, [Ahrens-Nicklas] really argued — she did not have to do much to convince me — that we needed to pivot to working on these most severe, devastating diseases: urea cycle disorders,” Musunuru said. “She realized that these therapies might be able to help the sickest of her patients who had terrible diseases so rare that each patient might be the only one in the world with a particular misspelling, a specific flaw in an enzyme.”

In the case of the Muldoons’ son, the physicians did not have 1 to 2 years to develop a medication like they had in previous trials. Musunuru said they gathered a team of academic and industry professionals to manufacture a custom medication within just 6 months.

During that 6-month span, the researchers developed a customized CRISPR/Cas9 gene-editing medication that would be delivered using messenger RNA, tested it in animal and cell models and received approval from the FDA for an investigational new drug application. CRISPR-based gene editing allows scientists to target and make desirable edits to the genome.

“We met early on with the FDA, and they were incredibly supportive,” Musunuru said. “They recognized it was an unusual circumstance [and] told us to do as good a job as we possibly could in the limited time we had, and they would take it from there.

“They honored that commitment when we formally submitted our application [and] approved it in just 1 week,” he said.

Exceeding expectations

Between age 6 and 7 months, Ahrens-Nicklas said the Muldoons’ son received a small dose of his custom IV treatment.

“Infusion day was terrifying and exciting at the same time,” she said. “It was an amazing moment when we were able to actually hold in our hands the treatment — a syringe of the medication that we had worked so hard to create.”

Although his parents and care team were nervous and excited, Ahrens-Nicklas said the Muldoons’ son was unfazed and slept through the 2-hour infusion.

Because the therapy had not been administered to an infant before, Ahrens-Nicklas said they started with a low dose (0.1 mg/kg) to ensure his safety. After the first dose, he was able to consume the recommended daily allowance of protein for a baby of his size. According to a related study published in The New England Journal of Medicine, his care team was also able to reduce his dosage of glycerol phenylbutyrate from 10.1 to 8.1 mL/square meter of body surface area per day after the first dose, but his glutamine levels began to rise a few weeks later, so he was put back onto his original dose.

In the study, Ahrens-Nicklas and colleagues wrote that he received a second, larger dose (0.3 mg/kg) 3 weeks after the first. After the second dose, his care team reduced his glycerol phenylbutyrate dose by half (10.1 to 5 ml per square meter per day).

“We just recently gave him his third and final planned dose, so we are still learning if it had any additional benefit,” Ahrens-Nicklas said. “But every day, he is showing us signs that he is growing and thriving.”

Although she said she would never use the word “cure,” Ahrens-Nicklas said the infant’s progress is reassuring. He is eating more protein, recently had a growth spurt, and is taking less medication than when he started. She could not say whether he will ever not need medication, but “he showed us that he is safer than he was before.”

Nicole Muldoon said her son exceeds her expectations every day. He is trying new foods, sitting up in his crib by himself and reaching other important milestones.

“It blows us away even more because we know what was stacked up against him in the very beginning and how bad of a prognosis it was in the beginning for him,” she said.

‘The future of medicine’

Although it is still too early to see the long-term effects of this bespoke therapy, Peter Marks, MD, PhD, who recently retired as director of the FDA’s Center for Biologics and Evaluation and Research, said the case demonstrated a possible way forward in developing personalized medicine.

“There could be hundreds to thousands of diseases that could be treated through an approach similar to [this one],” he wrote. “That is, the combination of rapid diagnosis through genome sequencing and expedited individualized product development, followed by administration of the therapy and careful monitoring of safety and efficacy outcomes, could remarkably improve the lives of persons affected by these rare disorders.”

Marks said it may be possible for companies to develop a therapy for a rare disease and then get regulatory approval for the overall approach, which would streamline development of disease-specific drugs and reduce costs.

“I do not think I am exaggerating when I say this is the future of medicine,” Musunuru said. “This is the first step toward the use of gene editing therapies to treat a wide variety of rare genetic disorders for which there are currently no definitive treatments and for which there are actually very few treatments currently in development at all.”

References:

For more information:

Rebecca C. Ahrens-Nicklas, MD, PhD, can be reached at ahrensnicklasr@chop.edu.

Kiran Musunuru, MD, PhD, can be reached at kiranmusunuru@gmail.com.


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