In Historic First, Gene Editing Helps Infant Beat Deadly Disease

PHILADELPHIA — In a medical first that could revolutionize treatment for thousands of rare genetic diseases, doctors have successfully used a custom-designed gene editing therapy to treat a baby boy born with a potentially fatal metabolic disorder. The landmark achievement represents the first time scientists have rapidly created a personalized gene-editing treatment for a single patient with an ultra-rare genetic condition.

The seven-month-old infant, named KJ, had a severe form of CPS1 deficiency, a metabolic disorder affecting only one in 1.3 million people. Without treatment, half of babies with this condition die in early infancy.

What happened next marks a watershed moment in medicine: instead of accepting the grim prognosis, a team of scientists and doctors raced against time to design, test, and deliver a customized gene-editing therapy specifically for the infant’s unique genetic mutation. The entire process—from diagnosis to treatment—took just six months.

Race Against Time: A Deadly Diagnosis

Doctors say KJ’s deficiency stems from two inherited genetic mutations that prevents his body from properly processing nitrogen waste in the blood, leading to dangerous ammonia buildups that can cause brain damage and death. Without a working copy of the CPS1 gene, which plays a crucial role in the urea cycle that removes nitrogen waste, the child faced a life-threatening situation.

Traditional treatments for CPS1 deficiency include severely restricted protein diets (since protein metabolism produces nitrogen waste) and medications that help remove nitrogen from the body. While liver transplants can provide a long-term solution, they’re often not feasible for infants who may suffer irreversible neurological damage before they’re large enough for surgery.

KJ’s condition was catastrophic from birth. Within 48 hours of life, he became lethargic and developed respiratory problems. Blood tests revealed ammonia levels greater than 1000 μmol per liter — more than 30 times the normal range — a life-threatening situation requiring immediate continuous renal-replacement therapy (a type of dialysis).

Rather than accepting this bleak outlook, doctors and scientists from the University of Pennsylvania, Children’s Hospital of Philadelphia, and several other institutions formed a team to attempt something unprecedented.

Creating a Custom Genetic Treatment

The medical team’s solution was as elegant as it was revolutionary. They used a technology called base editing—a more precise version of CRISPR gene editing—to correct one of the baby’s specific CPS1 mutations. The treatment, delivered via lipid nanoparticles (tiny fat bubbles that can carry genetic material into cells), was designed to target the liver cells where the CPS1 enzyme normally functions.

Doctors worked at breakneck speed to help the infant survive his condition:

• Within one month: They developed cell models with the baby’s mutation
• By two months: They’d identified the best editing approach
• At five months: They completed safety testing in monkeys
• At six months: They manufactured clinical-grade therapy and received FDA approval

After extensive laboratory testing and safety studies in animals, KJ received two intravenous infusions of the therapy—named “k-abe”by the researchers—at approximately 6 and y months of age. The paper documenting their work is published in the New England Journal of Medicine.

Remarkable Results and Future Promise

KJ received his first infusion in February 2025, with follow-up doses in March and April. Within seven weeks of the first treatment, his condition improved dramatically. He tolerated more protein in his diet and required only half his previous dose of ammonia-removing medication (glycerol phenylbutyrate).

Most telling was his response to viral illnesses. Before treatment, such infections would likely trigger dangerous ammonia spikes. Afterward, he weathered multiple viral infections without crisis, even continuing his full-protein diet throughout.

“Years and years of progress in gene editing and collaboration between researchers and clinicians made this moment possible, and while KJ is just one patient, we hope he is the first of many to benefit from a methodology that can be scaled to fit an individual patient’s needs,” said Dr. Rebecca Ahrens-Nicklas, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program at CHOP and an assistant professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania, in a statement.

The adaptability of this approach holds significant potential. As the researchers wrote in their paper: “Therapies similar to k-abe could be developed for hundreds of hepatic inborn errors of metabolism.” By keeping the delivery system and editing machinery the same while customizing the targeting component, doctors could create personalized treatments for many genetic conditions.

For families facing devastating diagnoses of ultra-rare genetic disorders, this breakthrough offers something previously unimaginable: hope. While longer follow-up is needed to confirm the treatment’s safety and effectiveness, this case demonstrates that personalized genetic medicine is now reality.

KJ’s parents, Kyle and Nicole Muldoon, expressed their relief and gratitude. “We would do anything for our kids, so with KJ, we wanted to figure out how we were going to support him and how we were going to get him to the point where he can do all the things a normal kid should be able to do,” Nicole said. “We thought it was our responsibility to help our child, so when the doctors came to us with their idea, we put our trust in them in the hopes that it could help not just KJ but other families in our position.”

The doctors plan to continue monitoring the young patient while refining their approach for future cases. For now, a family that faced overwhelming odds has watched their son grow from the 9th percentile in weight to the 26th percentile during the study period — an encouraging sign when many experts might have expected a much worse outcome.

Paper Summary

Methodology

The researchers developed a customized gene editing therapy for a baby diagnosed with severe carbamoyl-phosphate synthetase 1 (CPS1) deficiency, a rare urea cycle disorder. After sequencing the patient’s genome to identify two specific CPS1 mutations, the team screened various adenine base editors (ABEs) to identify the most efficient approach for correcting one of these mutations (Q335X). They tested their therapy in cell models by creating a human cell line with the patient’s mutation, then validated the approach in mice engineered to carry the human mutation sequence. After determining safety in a limited study with cynomolgus monkeys, they manufactured clinical-grade therapy and administered it to the patient twice (at 0.1 mg/kg and 0.3 mg/kg) at 7 and 8 months of age, following FDA approval of a single-patient expanded-access Investigational New Drug application.

Results

After receiving the gene editing therapy, the patient showed clinical improvement that suggested partial correction of the enzyme deficiency. Within 7 weeks of the first treatment, the baby tolerated increased dietary protein intake and was able to reduce his dose of glycerol phenylbutyrate (a nitrogen-scavenging medication) to half the starting dose. The median blood ammonia levels decreased from 23 μmol/liter before treatment to 13 μmol/liter after the second dose. Perhaps most significantly, the patient weathered multiple viral illnesses without experiencing hyperammonemic crises that typically occur in patients with this condition. No serious adverse events occurred, although the patient experienced transient elevations in liver enzymes following the second dose and during viral illnesses.

Limitations

The study has several important limitations. The follow-up period was only 7 weeks after the initial infusion, so longer-term safety and efficacy remain unknown. The researchers couldn’t perform a liver biopsy to directly measure the rate of gene correction in the patient’s hepatocytes due to safety concerns in the infant. The potential for germline editing with the therapy couldn’t be evaluated. Additionally, this was a single-patient study without controls, making it difficult to definitively attribute all improvements to the therapy versus other aspects of the patient’s care.

Funding and Disclosures

The study was supported by grants from the National Institutes of Health and additional funding from the Children’s Hospital of Philadelphia Research Institute’s Gene Therapy for Inherited Metabolic Disorders Frontier Program. In-kind contributions were made by Acuitas Therapeutics, Integrated DNA Technologies, Aldevron, and Danaher. Several authors disclosed relationships with these companies and other biotechnology firms.

Publication Information

The paper titled “Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease” was published in the New England Journal of Medicine on May 15, 2025. The lead authors were Kiran Musunuru, M.D., Ph.D. and Sarah A. Grandinette, B.S., with Rebecca C. Ahrens-Nicklas, M.D., Ph.D. as the corresponding author.

This article by one of our Danaher Life Sciences thought leaders was originally published in StudyFinds. Shared here by permission.