Contributor: Alec Coston, MD

Educational Pearls:

Disclaimer: this has nothing to do with the ER but is too cool to not talk about.

Without treatment, typically fatal within the first few weeks of life
Even with current standard treatments, life expectancy is often limited to ~5–6 years

A team of researchers at the Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania developed the CRISPR-based targeted gene therapy for this patient.
First-of-its-kind precision approach tailored to the patient's specific mutation

Whole-genome sequencing to identify the exact CPS1 mutation
Creation of a custom base-editing enzyme designed to correct that specific mutation
Design of a guide RNA to direct the base editor to the precise genomic location

CPS1 is primarily expressed in hepatocytes
The liver is relatively easy to target with lipid nanoparticles
Hepatocytes divide frequently, allowing edited genes to be passed on as cells replicate

References

https://www.nih.gov/news-events/news-releases/infant-rare-incurable-disease-first-successfully-receive-personalized-gene-therapy-treatment
Choi Y, Oh A, Lee Y, Kim GH, Choi JH, Yoo HW, Lee BH. Unfavorable clinical outcomes in patients with carbamoyl phosphate synthetase 1 deficiency. Clin Chim Acta. 2022 Feb 1;526:55-61. doi: 10.1016/j.cca.2021.11.029. Epub 2021 Dec 29. PMID: 34973183.
Bharti N, Modi U, Bhatia D, Solanki R. Engineering delivery platforms for CRISPR-Cas and their applications in healthcare, agriculture and beyond. Nanoscale Adv. 2026 Jan 5. doi: 10.1039/d5na00535c. Epub ahead of print. PMID: 41640466; PMCID: PMC12865601.

Summarized and edited by Jeffrey Olson MS4