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

• 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

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