Prime editing efficiently corrects cystic fibrosis mutation in human lung cells

  • Art
  • July 11, 2024

Cystic fibrosis is one of the most common genetic disorders, causing thick mucus buildup in the lungs and other parts of the body, breathing problems and infections. A three-drug cocktail known as Trikafta has greatly improved patients’ quality of life since its development in 2019, but it can cause cataracts and liver damage and must be taken daily at a cost of about $300,000 a year.

Now, researchers from the Broad Institute of MIT and Harvard and the University of Iowa have developed a gene-editing approach that efficiently corrects the most common mutation that causes cystic fibrosis, which affects 85 percent of patients. With further development, it could pave the way for treatments that are administered only once and have fewer side effects.

The new method, published today in Nature Biomedical Technologyprecisely and durably corrects the mutation in human lung cells, restoring cell function to levels comparable to Trikafta. The approach is based on a technique called prime editing, which can create insertions, deletions and substitutions up to hundreds of base pairs long in the genome with few unwanted byproducts. Prime editing was developed in 2019 by the lab of David Liu, who is the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad, as well as a professor at Harvard University and an investigator of the Howard Hughes Medical Institute.

“We hope that using prime editing to correct the predominant cause of cystic fibrosis could lead to a one-time, permanent treatment for this serious disease,” said Liu, the study’s lead author. “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.”

Postdoctoral researcher Alex Sousa and doctoral student Colin Hemez, both from Liu's lab, were first authors of the study.

Gene repair

Cystic fibrosis is caused by mutations in the CFTR gene that blocks ion channels in the cell membrane that pump chloride out of cells. There are more than 2,000 known variants of the CFTR gene, 700 of which cause disease. The most common is a three-base pair CTT deletion, which causes the ion channel protein to misfold and break down.

Correcting the CTT deletion in CFTR has long been a target of gene-editing therapies by labs including Liu’s, but most efforts have not proven efficient enough to yield therapeutic benefit. Nor do they use approaches such as CRISPR/Cas9 nuclease editing, which generate double-strand breaks in the DNA that can cause unwanted changes to the target gene and elsewhere in the genome.

Prime editing, a more flexible and controlled type of gene editing that does not require double-strand breaks, could help address this limitation. To CFTR mutation, Liu’s team combined six different improvements to the technology. These included improving the prime editing guide RNAs that program prime editor proteins to find their target and make the desired edit, as well as tweaking the prime editor protein itself and other changes that make the target site more accessible. Combined, these refinements corrected about 60 percent of CTT deletions in human lung cells and about 25 percent in cells taken directly from patients’ lungs and grown in a dish, an increase over previous methods that corrected less than 1 percent of the mutation in cells. The new approach also generated 3.5 times fewer unwanted insertions and deletions per edit than previous methods using the Cas9 nuclease enzyme.

Next, researchers must develop ways to package and deliver the key processing machinery to the respiratory tracts of mice and eventually humans. The team hopes that recent advances such as lipid nanoparticles that reach the lungs of mice could speed up the translation of this approach.

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