medwireNews: A customized gene-editing approach has been used for the first time to treat a rare genetic condition in an infant, with encouraging results.
“After a neonate […] received a diagnosis of severe carbamoyl-phosphate synthetase 1 [CPS1] deficiency, a disease with an estimated 50% mortality in early infancy, we immediately began to develop a customized lipid nanoparticle–delivered base-editing therapy,” write the researchers in The New England Journal of Medicine.
The authors of an accompanying Science Behind the Study editorial – Andrea Gropman (St. Jude Children’s Research Hospital, Memphis, Tennessee, USA) and Alexis Komor (University of California, San Diego, La Jolla, USA) – explain that CPS1 deficiency is “one of the most severe and rarest urea-cycle disorders” that “typically manifests as profound hyperammonemia in the first 24 to 48 hours after birth.”
They add that “[c]linical interventions are limited and may include dialysis, ammonia scavengers, protein restriction, and, later in life, liver transplantation, but neurologic outcomes are often poor.”
In the case of this infant, the research team reports that once the therapy was administered, after obtaining regulatory approval, he “was able to receive an increased amount of dietary protein and a reduced dose of a nitrogen-scavenger medication to half the starting dose, without unacceptable adverse events and despite viral illnesses.”
To correct the identified genetic abnormality, namely the CPS1 Q335X variant, the investigators developed a specific adenine base editor that would be delivered intravenously in the form of a messenger RNA encapsulated in lipid nanoparticles. The therapy – named kayjayguran abengcemeran (k-abe) – was tested intensively including for editing efficiency in mice and for safety in nonhuman primates.
Prophylactic immunosuppression with sirolimus and tacrolimus was initiated a few days before the first infusion of k-abe at a total RNA dose of 0.1 mg/kg was given on day 208 after birth. Following treatment, it was possible to increase the baby’s dietary protein intake but not to wean him from the nitrogen-scavenger medication glycerol phenylbutyrate.
So, a second dose of k-abe at 0.3 mg/kg was given 22 days after the first infusion, and 2 weeks later, the dose of glycerol phenylbutyrate could be reduced to half the starting dose (from 10.1 to 5.0 mL/day) without adverse effects.
Kiran Musunuru (Children’s Hospital of Philadelphia, Pennsylvania, USA) and associates highlight that the median blood ammonia levels before the first k-abe infusion (23 µmol/L), between the two infusions (9 µmol/L), and after the second infusion (13 µmol/L) “support the occurrence of a treatment-related reduction.”
The baby’s weight increased, from 7.14 kg on day 207 after birth to 8.17 kg on day 256, the end of the 7-week follow-up period, going from the 9th percentile to the 26th percentile. And his neurological status remained stable.
The researchers acknowledge the limitations of the study, such as the fact that “[l]iver biopsy to assess for corrective CPS1 editing was deferred because it posed an unacceptable risk to the infant,” and the short follow-up.
They write: “[L]onger follow-up is needed to assess the safety and efficacy of k-abe, as well as the patient’s neurologic health.”
In conclusion, Musunuru and colleagues say that “[a]lthough k-abe was developed under emergency conditions for a devastating neonatal-onset metabolic disorder, we anticipate that rapid deployment of patient-specific gene-editing therapies will become routine for many genetic diseases.”
Gropman and Komor describe the study as “a milestone in the evolution of personalized therapies for rare and ultrarare inborn errors of metabolism.”
But they caution that it “must be balanced against the current limitations of an N-of-1 experience in a rare or ultrarare condition.”
The editorialists continue: “Although the authors noted clinical stabilization in the short term, the absence of direct molecular confirmation of gene editing by means of liver biopsy leaves questions unanswered, such as the durability of the therapeutic effect, the extent of mosaicism of editing, and the risks of off-target events or immune responses.
“Longer-term follow-up of this patient will be critical to obtaining answers.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of the Springer Nature Group
N Engl J Med 2025; doi:10.1056/NEJMoa2504747
N Engl J Med 2025; doi:10.1056/NEJMe2505721
