World’s First Personalized CRISPR Therapy Successfully Treats Infant with Rare Metabolic Disease

A Precision Breakthrough for CPS1 Deficiency

The patient, known as KJ, was born with severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a rare metabolic disorder that prevents the body from safely processing ammonia. Children with this condition are at high risk of brain and organ damage due to ammonia buildup, and treatment typically involves restrictive diets, medications, and, if the patient is old enough, liver transplantation.

In February 2025, at just over six months of age, KJ received a personalized CRISPR-based gene editing therapy designed to correct the underlying genetic defect. The therapy was well-tolerated, and he is now showing promising signs of improvement.

From Bench to Bedside in Record Time

The treatment was developed by Dr. Rebecca Ahrens-Nicklas, MD, PhD of Children´s Hospital of Philadelphia (CHOP) and Dr. Kiran Musunuru, MD, PhD of Penn Medicine, who co-led the effort. Their collaboration began in 2023, focusing on urea cycle disorders, a group of conditions including CPS1 deficiency.

With years of research into gene editing and rare metabolic conditions as a foundation, the team created a base editing therapy specific to KJ’s genetic variant. Delivered using lipid nanoparticles targeted to the liver, the experimental therapy was administered in February, followed by two additional doses in March and April 2025.

A detailed description of the therapy and clinical results appears in the latest issue of The New England Journal of Medicine, and the findings were presented at the American Society of Gene & Cell Therapy Annual Meeting in New Orleans.

Early Signs of Success

As of April 2025, KJ had received three doses of the therapy without serious side effects. Since the initial treatment, he has:

• Tolerated a higher-protein diet

• Required less nitrogen-scavenging medication

• Recovered from typical childhood infections, like rhinovirus, without dangerous ammonia accumulation

These early outcomes suggest improved metabolic function, though long-term monitoring will be needed to assess the therapy’s lasting effects.

The Bigger Goal: Expanding Personalized Therapies

While gene editing has shown promise in conditions like sickle cell disease and beta thalassemia, most rare diseases involve unique genetic variants that cannot be addressed by one-size-fits-all approaches. This case shows that customized CRISPR therapies can be developed for individual patients—potentially transforming care for the millions living with rare disorders.

Ahrens-Nicklas and Musunuru are part of the NIH-funded Somatic Cell Genome Editing Consortium, which aims to accelerate genome editing research and clinical translation. Their work suggests that personalized treatment development is not only feasible, but also scalable.

Family Impact: KJ’s Journey

KJ’s parents, Nicole and Kyle Muldoon, supported the decision to pursue experimental therapy. Until recently, KJ’s condition required intensive hospital care. A liver transplant was not yet an option due to his young age and health instability.

Now, KJ is home, reunited with his siblings, and showing encouraging signs of development. The family's story highlights the emotional and practical challenges families face when navigating rare diseases—and the hope that new science can offer.

Research Support and Future Directions

This pioneering study was supported by:

• NIH Somatic Cell Genome Editing Program

• Additional NIH grants and research infrastructure support from CHOP

• In-kind contributions from Acuitas Therapeutics, Integrated DNA Technologies, Aldevron, and Danaher Corporation

The team hopes their approach can be replicated by other academic centers to treat more rare conditions, expanding access to precision therapies.

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