CRISPR base editing has delivered a landmark n-of-1 gene therapy for an infant with carbamoyl phosphate synthetase 1 (CPS1) deficiency, in a clinical milestone that may redefine how rare genetic diseases are treated. CPS1 deficiency is a mitochondrial disorder caused by a loss-of-function mutation in the CPS1 gene that impairs the urea cycle and leads to life-threatening hyperammonaemia. The case, published in the New England Journal of Medicine on 15 May, represents the first successful application of personalised in vivo base editing to treat a monogenic disorder in a single patient, and potentially opens the door to a new model of therapeutic development.
The patient, referred to as KJ, was diagnosed shortly after birth with CPS1 deficiency. Without functional CPS1, toxic ammonia accumulates rapidly, risking severe neurological damage or death. Existing treatments, including dialysis, dietary restriction, ammonia scavengers, and liver transplantation, offer limited benefit and carry substantial risks.
KJ's therapeutic path diverged when researchers at the Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania, US, decided to pursue a personalised gene editing approach. Led by physician-scientist Rebecca Ahrens-Nicklas and geneticist Kiran Musunuru, the team used adenine base editing - a precision genome editing method - to correct the single G-to-A nonsense mutation (Q335X) on KJ’s paternal allele.
Using lipid nanoparticles (LNPs) to deliver the editor to liver cells, the team developed a bespoke therapy, kayjayguran abengcemeran (k-abe), named after the patient. The adenine base editor was optimised through an intensive screening process, involving dozens of guide RNA (gRNA) and editor combinations tested in custom-engineered human hepatocyte cell lines harbouring KJ’s mutation.
Preclinical validation included two transgenic mouse models and non-human primates, with data demonstrating both safety and on-target editing activity. The US Food and Drug Administration authorised compassionate use after an accelerated review, enabling a first-in-human dosing just six months after sequencing the patient’s genome.
While the initial ultra-low dose showed minimal clinical effect, subsequent administrations allowed clinicians to reduce KJ’s medication burden and loosen dietary restrictions. He has avoided a liver transplant - once considered inevitable - and now presents with a milder phenotype of his disease. The extent of gene editing in hepatocytes remains unknown, as liver biopsies are not feasible, but the observed metabolic improvements are encouraging.
Musunuru et al highlight the potential for base editing to serve as a durable cure for monogenic liver diseases, particularly those poorly addressed by conventional gene therapy due to gene size or turnover issues in paediatric livers. Still, they caution that evidentiary standards and regulatory frameworks must evolve to accommodate n-of-1 interventions, especially given the resource intensity involved.
The authors hope this case can serve as a springboard for a platform approach - where editors tailored for one mutation can be adapted quickly for others. Dr Ahrens-Nicklas cautions that more time is needed to “make definitive statements about how well [the therapy] worked”. Yet for now, KJ’s story stands as a groundbreaking proof-of-concept for genomic medicine’s next frontier.
By Rosie Bannister