One of the most prevalent hereditary diseases, cystic fibrosis, results in thick mucus in the lungs and other bodily organs, breathing difficulties, and infection. Trikafta is a three-drug cocktail developed in 2019 and has significantly improved patient quality of life. However, it must be taken daily at an approximate annual cost of $300,000 and can induce cataracts and liver damage.
Researchers at the University of Iowa, the Broad Institute of MIT, Harvard, and Harvard have now created a gene-editing method that effectively fixes the most prevalent mutation affecting 85% of patients, causing cystic fibrosis. It could open the door to therapies that only need to be given once and have fewer negative effects with future research.
Their findings were published in the journal Nature Biomedical Engineering.
Accurately and permanently fixes the mutation in human lung cells, bringing back cell function that is comparable to Trikafta. The method is based on a process known as prime editing, which may modify the genome in a way that produces minimal undesirable side effects while making insertions, deletions, and substitutions up to hundreds of base pairs long. Prime editing was created in 2019 at the lab of David Liu, a Howard Hughes Medical Institute scientist, Harvard University professor, Richard Merkin Professor, and head of the Broad’s Merkin Institute of Transformative Technologies in Healthcare.
We are hopeful that the use of prime editing to correct the predominant cause of cystic fibrosis might lead to a one-time, permanent treatment for this serious disease,
Developing a strategy to efficiently correct this challenging mutation also provided a blueprint for optimizing prime editing to precisely correct other mutations that cause devastating disorders.
David Liu
Mutations in the CFTR gene disrupt ion channels in the cell membrane, which pump chloride out of cells and cause cystic fibrosis. Seven hundred of the more than 2,000 identified CFTR gene variations are associated with illness. The most frequent is a CTT deletion of three base pairs, which results in the misfolding and degradation of the ion channel protein.
The goal of gene-editing therapies, including Liu’s, has long been to correct the CTT deletion in CFTR. However, most attempts to do so have not been effective enough to provide a therapeutic benefit, or they have used methods like CRISPR/Cas9 nuclease editing, which creates double-stranded breaks in DNA and can lead to unintended changes in the target gene and other parts of the genome.
This restriction could be overcome with the use of prime editing, a more regulated and adaptable kind of gene editing that does not call on double-stranded breaks. Liu’s team integrated six distinct technological advancements to more effectively cure the CFTR mutation. These included tweaking the prime editor protein itself and making other adjustments that provide easier access to the target site, as well as enhancing the prime editing guide RNAs that instruct prime editor proteins to locate their target and perform the intended edit. Combined, these improvements improved upon earlier techniques that repaired less than 1% of the mutation in cells, correcting over 60% of the CTT deletions in human lung cells and roughly 25% in cells isolated from patient lungs and cultured in a dish. Comparing the new procedure to earlier techniques that employed the Cas9 nuclease enzyme, it also produced 3.5 times fewer undesired insertions and deletions per edit.
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Subsequently, scientists must devise strategies for encasing and delivering cutting-edge editing equipment to mice’s and eventually people’s airways. The group is optimistic that discoveries like lipid nanoparticles that enter mice’s lungs may hasten the use of this strategy.
Source: BROAD Institute News
Journal Reference: Sousa, Alexander A., et al. “Systematic Optimization of Prime Editing for the Efficient Functional Correction of CFTR F508del in Human Airway Epithelial Cells.” Nature Biomedical Engineering, 2024, pp. 1-15, https://doi.org/10.1038/s41551-024-01233-3.
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