A Medical First: Personalized Gene-Editing Treatment for an Infant

Less than 48 hours after KJ Muldoon’s birth in August 2024, it became evident that something was seriously wrong. He was unusually lethargic and struggled with breathing. Blood tests revealed dangerously high levels of ammonia, and further testing confirmed a deficiency in the CPS1 enzyme — an extremely rare genetic disorder where one in two patients dies within the first few months of life. Those who survive often experience developmental delays and intellectual disabilities.

Once diagnosed, KJ’s doctors immediately began a race to develop a personalized gene therapy to correct the specific error in his genetic code. Remarkably, they succeeded in just six months, making young Muldoon the first person ever to receive a gene-editing therapy tailored exclusively for him. This achievement paves the way for personalized gene therapies for rare genetic disorders that are currently deemed untreatable.

 Ammonia Toxicity

KJ, the fourth child of Nicole and Kyle Muldoon, was born a few weeks early in Pennsylvania and initially appeared healthy. However, shortly after birth, he began showing symptoms that led doctors to suspect meningitis or sepsis — a severe and life-threatening response to a blood infection. Thanks to the vigilance of his caregivers, dangerously high levels of ammonia were detected in his blood, and the doctors quickly realized that his critical condition was not caused by an infection.

The infant was transferred to the Children’s Hospital of Philadelphia (CHOP), where the medical team began treatment to remove the excess ammonia from his body. At the hospital, KJ’s genome was sequenced, revealing a defect in both copies of the gene responsible for producing the CPS1 enzyme. This meant his body could not produce the enzyme, which plays a crucial role in the urea cycle — the body's process of eliminating ammonia, a toxic byproduct of protein breakdown, by converting it into urea.

In healthy individuals, ammonia is converted into urea in the liver, enters the bloodstream, and is then filtered by the kidneys and excreted in the urine. But for those lacking a functioning CPS1 enzyme, ammonia accumulates in the body to toxic levels. This condition is life-threatening because ammonia is especially harmful to nerve cells and can cause brain damage, coma, and death. It is also an extremely rare condition, affecting only one in every 1.3 million newborns.

Treatment for CPS1 deficiency typically involves reducing protein intake in the patient’s diet and administering medications that help eliminate ammonia — until the child is old enough for a liver transplant with a functioning urea cycle. However, during this time, spikes in ammonia levels — such as those triggered by infections — can lead to irreversible brain damage or death.

 

Ammonia accumulated in his body, reaching toxic levels. KJ during hospitalization | Photo: Children's Hospital of Philadelphia

As Quickly as Possible

 “When we Googled CPS1 deficiency, we saw there were two likely outcomes – a liver transplant or death,” said Nicole, KJ’s mother. “We were in shock.” Faced with this devastating reality, she and her partner decided to keep KJ hospitalized for as long as necessary, so he could receive  round-the-clock care to maximize his chances of survival. Due to his critical condition, KJ was placed on the liver transplant waiting list at just five months old — a transplant that might arrive too late.

Meanwhile, KJ’s medical team began working on a potential treatment that might be able to repair one of the defective copies of his gene in the liver. Rebecca Rebecca Ahrens-Nicklas, a physician and researcher at the Children’s Hospital of Philadelphia, and Kiran Musunuru, a doctor and geneticist at the University of Pennsylvania, along with their colleagues, described the race to develop the gene therapy in a paper published in the New England Journal of Medicine.

Ahrens-Nicklas and Musunuru have been collaborating for several years in an effort to find ways to correct genetic errors — mutations — in the livers of children suffering from urea cycle disorders. Their focus was on base editing, a CRISPR-based gene-editing enables the alteration of a single base, or “letter”, in DNA. The CRISPR system, which scientists began using only in the past decade, has revolutionized genetic engineering. It enables easy and rapid gene editing and is often described as "genetic scissors" that cut both strands of the DNA. In contrast, base editing is more like using an eraser and pencil — it makes a small nick in one DNA strand, enabling the replacement of a single base.

To help children born with urea cycle disorders, mutations must be corrected as early as possible, before irreversible damage occurs. To that end, Ahrens-Nicklas and Musunuru developed a workflow to accelerate the production of a personalized base-editing system from the moment a patient’s disease-causing mutation is identified. The researchers had practiced the process, selecting a known genetic error that causes a urea cycle disorder and working as fast as possible to develop a suitable editor. In each trial, they managed to reduce the time required to find a solution — from over a year to just a few months.

KJ’s mutation was the seventh they attempted to rapidly correct — but this time, it wasn’t just a lab exercise. This time, it was a real, sick baby.

 

The genetic changes in other regions of the DNA were not harmful. Two researchers examining where base editing alters the genetic sequence | Photo: Innovative Genomics Institute

 

A Race Against Time

Ahrens-Nicklas, Musunuru, and their team — in collaboration with researchers from the Innovative Genomics Institute (IGI) at the University of California, Berkeley, several biotechnology companies, and with federal funding from the U.S. National Institutes of Health (NIH) — developed a gene therapy for KJ in record time. They worked almost nonstop, including through holidays. By the time KJ was one month old, the researchers had already grown cell cultures carrying his specific mutation to test the treatment. A month later, they had a working base-editing system.

The system is encased in a tiny fatty bubble (lipid nanoparticle) that protects it and helps it enter liver cells. Inside the bubble are the instructions for producing the editor, along with a small genetic sequence (gRNA) that guides the editor precisely to the location where the incorrect letter in one copy of KJ’s gene needs to be corrected. This sequence was named “kayjayguran” after the baby.

COVID-19 vaccines use similar lipid bubbles, though they don’t carry instructions to alter genetic sequences. Instead, they temporarily instruct cells at the injection site to produce a specific viral protein.

Five months after KJ’s birth, the completed gene therapy — named “k-abe” — was tested on cell cultures and genetically engineered mice carrying the defective gene. The treatment successfully corrected the mutation. However, as it often happens with the CRISPR system, it also caused some unintended changes in other regions of the DNA. Fortunately, tesging showed that these off-target genetic changes did not cause harm. It is similar in a way to correcting a typo in the sentence “Cats have many supestitions,” so it reads “Kats have many superstitions” after the correction. The change outside the word “superstitions” doesn’t alter the meaning of the sentence and, therefore, is harmless.

At the same time, the researchers were also testing the therapy’s safety in a macaque monkey. When KJ was six months old, the researchers submitted the test results and an application to the U.S. Food and Drug Administration (FDA) for approval of the therapy as an investigational new drug for a single patient. The FDA approved the request within a week, and several biotech companies collaborated to produce the treatment at cost and at a quality suitable for human use.

 

The treatment made his disease significantly milder.
KJ after treatment, with two of the researchers who treated him — Rebecca Ahrens-Nicklas (right) and Kiran Musunuru | Photo: Children's Hospital of Philadelphia

 

New Hope

Once the researchers knew they had an approved treatment, Ahrens-Nicklas finally told KJ’s parents that she might have good news.  “My biggest fear in all of this was giving false hope to a family,” she said.

Nicole and Kyle chose to go ahead with the treatment.  “Our child was sick. We either had to have a liver transplant or give him this medicine that’s never been given to anybody before,” Kyle said. “It was an impossible choice, but we felt this was the best possible scenario for a life that, at one point, we didn’t know if he would be able to have.”

On February 25, six-month-old KJ received his first infusion — the first of three approved doses — at a very low dose. In March and late April, he received two more infusions at higher doses. His condition improved almost immediately: he was able to eat more protein, his medication dose was cut in half, and even viral infections didn’t cause spikes in his blood ammonia levels — a typical reaction for patients like him. He also gained weight, jumping from the 7th percentile just before the first infusion to the 40th percentile now, at 9.5 months old. In addition, KJ is no longer currently on the liver transplant list, although it’s still uncertain if he might need one in the future.

The treatment did not cure him, but it significantly reduced the severity of his disease. “While KJ will need to be monitored carefully for the rest of his life, our initial findings are quite promising,” Ahrens-Nicklas said in a press release.

Only a few weeks have passed since his last infusion, and it’s still too early to determine whether KJ’s improvement will be sustained over time, whether there will be any long-term side effects, or whether he will eventually be able to stop taking ammonia-clearing medications.  Additionally, there is no way to determine the exact success rate of the gene editing in KJ’s liver or whether any unintended genetic changes occurred. To assess this, researchers would need to perform a liver biopsy, which is too risky for a baby of his age.

Still, thanks to the treatment and his dramatic improvement, KJ no longer requires full-time hospitalization and will soon be going home. “We’re so excited that we’ll finally all be together at home,” said Kyle. “So that KJ can be with his siblings — and we can finally breathe again.”

 A video by the Children's Hospital of Philadelphia about the groundbreaking treatment - 

One Out of Many

The treatment KJ received is specifically tailored for him, designed to address the single mutation in his CPS1 gene. It cannot help other patients with the same enzyme deficiency if their disease is caused by a different mutation in the gene. However, its success offers hope that this method can be adapted for the rapid development of personalized gene therapies for patients with rare diseases.

Estimates suggest there are over 10,000 rare diseases. While each one is individually rare, together they affect about 300 million people worldwide as of 2024. More than 80% of rare diseases are genetic, and the majority affect children. A very large portion of these diseases currently lacks treatment, partly because it has not been financially viable for companies to invest the time and resources required to develop drugs for such small patient populations.

The hope of KJ’s medical team — and of other groups working on similar therapies — is that most components of the gene therapy could remain the same, while certain elements, like the small genetic sequence that directs the editor to its target, could be personalized for each patient. This approach could potentially bypass some regulatory steps currently required for treatment approval, further shortening development time and reducing costs.

How much does it cost to develop such a treatment? It's hard to say. The development budget for KJ’s therapy was part of a larger NIH-funded research project. Musunuru told MIT Technology Review that the development effort involved more than 45 physicians and scientists, along with pro bono assistance from several biotechnology companies. He estimates the eventual cost of gene-editing treatments might be similar to that of liver transplants — around $800,000.The Importance of Public Investment

The development of KJ’s treatment was also made possible by the openness of the FDA’s Center for Biologics Evaluation and Research, which is responsible for regulating such therapies. In an editorial published alongside the article by Ahrens-Nicklas, Musunuru, and their colleagues, the center’s director, Peter Marks, wrote that he had adopted “an advanced regulatory approach aimed at safely accelerating the development and availability of life-saving drugs.” However, in March of this year, Marks was forced to resign after attempting to defend the FDA against actions taken by U.S. Secretary of Health Robert F. Kennedy Jr. It is now unclear whether the center will continue to support personalized gene therapies.

The administration’s cuts to research funding and the NIH budget also raise concerns about the future of gene therapies in particular, and the future of scientific research in the U.S. more broadly. KJ’s treatment would not have been possible without federal investment — both in the treatment itself and in the many years of research that preceded it.

The CRISPR system was discovered through basic research— federally funded — on the immune system of bacteria against viruses. The development of CRISPR into a gene-editing tool was also largely supported by public investment. Federally funded research also led to the sequencing of the human genome and the development of base editing — both essential capabilities for creating KJ’s treatment. Even the search for and development of the therapy were funded by federal government budgets.

“This provides a compelling and timely lesson of the value of long-term investments in biomedical research, now under significant attack in the United States,” concluded Francis Collins, former director of the NIH, in an interview with The Washington Post. “The breathtaking campaign to save the life of this baby boy would never have been possible without strong research universities and decades of government support of fundamental and translational research by NIH and FDA.”

The article was originally published on Noam's Ark - Biological Thoughts”