Personalized CRISPR Therapy Successfully Treats Infant With Rare, Incurable CPS1 Deficiency

A personalized gene-editing therapy was safely delivered to an infant with a life-threatening, incurable genetic disease, explained Kiran Musunuru, MD, PhD, during a presentation at the 2025 American Society of Gene & Cell Therapy Annual Meeting (ASGCT 2025), held May 13-17 in New Orleans. Marking the first time this technology has been successfully administered as treatment for a human, the therapy development and delivery process took just six months from diagnosis (carbamoyl phosphate synthetase 1 [CPS1] deficiency) to treatment. No treatment-related adverse events were observed.

CPS1 is a rare disorder in the family of urea cycle disorders (UCDs) that results in excessive accumulation of nitrogen, in the form of ammonia, in the blood (2). Symptoms include vomiting, worsening lethargy, refusal to eat, and coma.

A First for CRISPR

Led by Dr Musunuru, at team of researchers from the Perelman School of Medicine at the University of Pennsylvania (UPenn) and the Children’s Hospital of Philadelphia (CHOP) developed the custom treatment using clustered regularly interspaced short palindromic repeats (CRISPR), a gene-editing platform that can be adapted to address a broad spectrum of genetic disorders, paving the way for personalized treatments in various parts of the body. Published simultaneously in the New England Journal of Medicine (NEJM), the research details the first documented use of a personalized CRISPR-based therapy given to a single patient, deliberately designed to alter only somatic (non-reproductive) cells, so that the genetic modifications would not be passed on and would impact only the treated individual (3).

“We were very concerned when the baby got sick, but the baby just shrugged the illness off,” said Dr Musunuru (1). Indeed, the baby’s disorder de-escalated from severe to mild, enabling the toleration of a more protein-rich diet. Support was provided by Acuitas Therapeutics in the form of a clinically vetted lipid nanoparticle delivery (LNP) vehicle that is safe to administer to newborns. The LNP allowed for three increasingly larger doses of the therapy.

Safe & Effective

“We knew the method used to deliver the gene-editing machinery to the baby’s liver cells allowed us to give the treatment repeatedly,” said CHOP pediatrician and study co-author Rebecca Ahrens-Nicklas, MD, PhD (1). “That meant we could start with a low dose that we were sure was safe.”

Indeed, the team observed indications of therapy effectiveness following the initial dose, when the six-month-old was able to eat more protein and anti-UCD medications could be safely reduced. Additionally, the baby was able to battle a cold and, later, a gastrointestinal infection, both of which would normally be incredibly dangerous for patients with CPS1.

“As a platform, gene editing—built on reusable components and rapid customization—promises a new era of precision medicine for hundreds of rare diseases, bringing life-changing therapies to patients when timing matters most: Early, fast, and tailored to the individual,” noted Joni L. Rutter, PhD, director of the National Institute of Health’s National Center for Advancing Translational Sciences.

Though promising, Dr. Musunuru and colleagues note in NEJM that “longer follow-up is warranted to assess safety and efficacy” (3).

Key Takeaways

This is a watershed moment for drug and biopharma manufacturing scientists, indicating a shift toward:

• Precision, patient-specific treatments.
• Agile, modular, and responsive manufacturing models.
• A broader pipeline of ultra-rare disease therapies, backed by a reusable and adaptable gene editing platform.

It’s a call to prepare for a future where treatments are not only biologically engineered but custom-built for individuals, potentially redefining how medicine is manufactured, regulated, and delivered.

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References:

• NIH. Infant with rare, incurable disease is first to successfully receive personalized gene therapy treatment. Press release. May 15, 2025.
• National Organization of Rare Disorders. Carbamoyl Phosphate Synthetase 1 Deficiency. Accessed May 16, 2025.
• Musunuru K, Grandinette S, Wang X, et al. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease. N Engl J Med. 2025, May 15. [Online ahead of print].