Prime editing-mediated readthrough of premature termination codons
| PERT (Prime editing-mediated readthrough of premature termination codons) | |
|---|---|
| Specialty | Medical genetics, gene therapy, molecular biology |
| Uses | Correction of nonsense mutations in genetic diseases |
| Types | genome-editing technique |
Prime editing-mediated readthrough of premature termination codons (PERT) is a genome-editing strategy that corrects nonsense mutations. The method converts non-essential endogenous transfer RNA (tRNA) into a suppressor tRNA. Upon translation this allows readthrough of premature stop codons. The mechanism targets the general molecular mechanism of ribosomal recognition of premature stop codons and is therefore described to be disease-independent.[1] Prime editing is one of the three classes of genome-editing technologies in mammalian cells. The other two are CRISPR-associated nucleases and base editors.[2]
Principle of the method
Many genetic diseases, such as cystic fibrosis and Duchenne muscular dystrophy are caused by nonsense mutations in a gene. This causes the production of a non-functional protein via protein translation. PERT uses a method called prime editing. Small changes inside living cells can be made by programmable nickase fused to a polymerase and a small guide RNA.[3] A recent review suggests functional outcomes should also be considered in context of the structural features of designed tRNA beyond anticodon changes.[4]
Development
PERT was first described in November 2025 in a "Nature" paper.[1] A proof-of-concept study showed that the method is able to restore functional protein production in disease contexts such as cystic fibrosis.[5][6]Prior research on suppressor tRNA has optimized the structural principles guiding PERT design[7]
Applications
PERT has been shown to restore protein production and function in cells and animal models.[5] PERT has been proposed for gene therapy applications.[8][9] PERT may be beneficial for larger patient cohorts since a single suppressor tRNA might be applicable across multiple diseases.[10][11]
References
- 1 2 Pierce, Sarah E.; Erwood, Steven; Oye, Keyede; An, Meirui; Krasnow, Nicholas; Zhang, Emily; Raguram, Aditya; Seelig, Davis; Osborn, Mark J.; Liu, David R. (2025). "Prime editing-installed suppressor tRNAs for disease-agnostic genome editing". Nature. 648 (8092): 191–202. Bibcode:2025Natur.648..191P. doi:10.1038/s41586-025-09732-2. PMC 12675287. PMID 41261131.
- ↑ Zhao, Zhihan; Shang, Peng; Mohanraju, Prarthana; Geijsen, Niels (2023). "Prime editing: advances and therapeutic applications". Trends in Biotechnology. 41 (8): 1000–1012. doi:10.1016/j.tibtech.2023.03.004. PMID 37002157.
- ↑ Chen, Peter J.; Liu, David R. (2022). "Prime editing for precise and highly versatile genome manipulation". Nat Rev Genet. 24 (3): 161–177. doi:10.1038/s41576-022-00541-1. PMC 10989687. PMID 36344749.
- ↑ Awawde, Aya; Radecki, Alexander A.; Vargas-Rodriguez, Oscar (2024). "Suppressor tRNAs at the interface of genetic code expansion and medicine". Frontiers in Genetics. 15 1420331. doi:10.3389/fgene.2024.1420331. PMC 11116698. PMID 38798701.
- 1 2 Zusi-Tran, Karen (19 November 2025). "Single prime editing system could potentially treat multiple genetic diseases". BROAD Institute. Retrieved 13 December 2025.
- ↑ Belluck, Pam; Zimmer, Carl. "New Gene-Editing Strategy Could Help Development of Treatments for Rare Diseases". New York Times. Retrieved 15 December 2025.
- ↑ Albers, Suki; Allen, Elizabeth C.; Bharti, Nikhil; Davyt, Marcos; Joshi, Disha; Perez-Garcia, Carlos G.; et al. (2023). "Engineered tRNAs suppress nonsense mutations in cells and in vivo". Nature. 618 (7966): 842–848. Bibcode:2023Natur.618..842A. doi:10.1038/s41586-023-06133-1. PMC 10284701. PMID 37258671.
- ↑ Oldach, Laurel (20 November 2025). "Prime Editing Boosted by Suppressor tRNAs". Bioengineer.org. Retrieved 13 December 2025.
- ↑ "Prime editing suppressor transfer RNAs for gene therapy". Chemical & Engineering News. 19 November 2025. Retrieved 13 December 2025.
- ↑ "New Approach Could Make Gene-Editing Treatments Faster and Cheaper". Power Health. 21 November 2025. Retrieved 13 December 2025.
- ↑ Grinstein, Jonathan D. (20 November 2025). "Reporter's Notebook: The Dawn of Disease-Agnostic Gene Editing Therapies". Retrieved 13 December 2025.