By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.May 20 2025
In a global first, scientists have used advanced base editing to repair a deadly gene mutation in a newborn, marking a major leap forward in the treatment of rare inherited metabolic diseases.
Study: Personalized Gene Editing to Treat an Inborn Error of Metabolism. Image Credit: Shutterstock AI Generator / Shutterstock.com
In a recent New England Journal of Medicine report, researchers describe a revolutionary gene editing technology that has been used to treat an infant with carbamoyl-phosphate synthetase 1 (CPS1) deficiency.
What is CPS1 deficiency?
The CPS1 gene encodes for CPS1, a mitochondrial enzyme that facilitates the reaction between ammonia and bicarbonate to produce carbamoyl phosphate. The loss of CPS1 prevents this crucial detoxification step of the urea cycle from occurring, subsequently leading to the rapid accumulation of ammonia within the bloodstream.
Due to the neurotoxic effects of ammonia, CPS1 deficiency can lead to long-term neurological deficits such as developmental delays and intellectual disabilities, as well as an increased risk of hyperammonemic encephalopathy, lethargy, seizures, coma, and death.
CPS1 deficiency is an autosomal recessive inborn error of metabolism, a type of genetic disorder caused by a genetic mutation that leads to a dysfunctional metabolic pathway. Current estimates indicate that between one in every 800,000 and one in every 1.3 million newborns will be diagnosed with CPS1 deficiency between 24 and 28 hours after birth.
Over 300 mutations have been identified on the CPS1 gene, the most common of which are missense mutations that lead to a single amino acid change in this protein. Nonsense mutations have also been frequently reported in CPS1 deficiency, which leads to the generation of a premature stop codon and, as a result, complete loss of function for this protein.
Hyperammonemia can be observed within 24 to 48 hours after birth, with current treatments including dialysis, ammonia scavenger therapy, protein restriction, and liver transplantation.
What is base editing?
The clinical application of conventional gene therapy for correcting CPS1 deficiency is associated with numerous challenges. Alternatively, base editing has emerged as an ideal solution to correct the genetic mutation that leads to CPS1 deficiency.
In the current study, researchers developed a base-editing strategy in which a guide ribonucleic acid (gRNA) molecule brings the modified clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) enzyme to the mutant CPS1 nucleotide. Both gRNA and Cas9 function as an adenine base editor (ABE) to convert the adenine (A)-thymine (T) base pair on the non-coding strand into guanine (G)- cytosine (C) base pair to correct the original mutation on the coding strand from pathological T to G.
The success of base-editing relies on the protospacer adjacent motif (PAM), a three-base motif that must be present for Cas9 nickase (Cas9n) binding. After binding, the A nucleotide in the PAM is deaminated, which subsequently allows the A-T base pair to be converted to the correct G-C base pair.
Base editing offers numerous advantages over CRISPR-Cas9 editing, which creates a DNA double-strand break (DSB) that is followed by either non-homologous end joining (NHEJ) or homology-directed repair (HDR) repair pathways. For example, while efficient in knocking out or inserting new genes, CRISPR-Cas9 editing relies on the cell's inherent DNA repair capabilities. Rather than cutting DNA, base editing utilizes an enzyme to chemically convert a single nucleotide base into another, thereby increasing the safety and precision of this approach.
Outcomes and future directions
Preclinical evaluation of this novel base-editing strategy involved both in vitro and in vivo studies, which led to the identification of a single combination of both the adenine base editor (ABE) and patient-specific gRNA that exhibited the greatest efficacy and precision. These studies demonstrated that the ABE successfully changed the mutant A into an inosine that resembles G on the non-coding strand, which ultimately led to the production of a full-length CPS1.
Long-term follow-up of this patient will be crucial to monitor for any off-target effects or immune responses and ensure the durability of its therapeutic effect. Additional studies are also needed to examine editing efficiency in liver biopsy samples after treatment.
For patients with CPS1 deficiency and similar ultrarare disorders, the findings offer hope and yet require validation through treatment of the second patient, the third, and beyond."
Journal reference: Gropman, A. L., & Komor, A. C. (2025). Personalized Gene Editing to Treat an Inborn Error of Metabolism. New England Journal of Medicine. doi:10.1056/NEJMe2505721, https://www.nejm.org/doi/full/10.1056/NEJMe2505721