Contributor: Alec Coston, MD
Educational Pearls:
Disclaimer: this has nothing to do with the ER but is too cool to not talk about.
Condition: Carbamoyl phosphate synthetase 1 (CPS1) deficiency
Rare inborn error of metabolism
Inability to properly break down ammonia
Leads to severe hyperammonemia and hepatic encephalopathy
Natural history:
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
Breakthrough treatment:
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
Key components of the therapy:
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
Delivery method:
Lipid nanoparticles used to deliver the gene-editing machinery
Nanoparticles can be targeted to specific tissues
Why the liver works well:
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
Long-term impact:
Once edited, cells continue producing functional CPS1 enzyme
Potential for durable, possibly lifelong correction from a single treatment
References
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
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