Breakthrough treatment corrects common mutation causing cystic fibrosis

Cystic fibrosis, a common genetic disorder, causes thick mucus build-up in the lungs and other parts of the body, leading to breathing problems and infections. A three-drug treatment known as Trikafta has significantly improved the quality of life for patients since 2019. However, it can cause cataracts and liver damage and costs around $300,000 annually.

Researchers at the Broad Institute of MIT and Harvard, along with the University of Iowa, have developed a new gene-editing approach that efficiently corrects the most common mutation causing cystic fibrosis, present in 85 percent of patients. This method could potentially lead to treatments that are administered only once and have fewer side effects.

The study, published in Nature Biomedical Engineering, shows that this new method precisely and durably corrects the mutation in human lung cells, restoring cell function to levels similar to those achieved with Trikafta. This approach uses prime editing, a technique that allows for precise changes in the genome without causing unwanted byproducts. Prime editing, developed in 2019 by David Liu's lab, can make insertions, deletions, and substitutions of up to hundreds of base pairs in the genome.

David Liu, the senior author of the study and a professor at Harvard University, stated, “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.” Liu also noted that developing this strategy provides a blueprint for correcting other mutations that cause devastating disorders.

The study's first authors, postdoctoral researcher Alex Sousa and graduate student Colin Hemez, both from Liu’s lab, have contributed significantly to this breakthrough.

Cystic fibrosis results from mutations in the CFTR gene, which impair ion channels in the cell membrane responsible for pumping chloride out of cells. There are over 2,000 known variants of the CFTR gene, with 700 causing disease. The most common mutation is a three base-pair CTT deletion, leading to a misfolded and degraded ion channel protein.

Gene-editing therapies have long aimed to correct the CTT deletion in the CFTR gene, but previous attempts have not been efficient enough or have used methods like CRISPR/Cas9 nuclease editing that can cause unwanted changes in the genome. Prime editing offers a more controlled form of gene editing without the need for double-stranded breaks.

Liu’s team made several enhancements to prime editing technology to correct the CFTR mutation more efficiently. These included improving the prime editing guide RNAs, modifying the prime editor protein, and making the target site more accessible. These refinements resulted in the correction of about 60 percent of the CTT deletions in human lung cells and about 25 percent in cells taken directly from patient lungs. This marks a significant improvement 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 compared to methods using the Cas9 nuclease enzyme.

The next step for researchers is to develop ways to package and deliver the prime editing machinery to the airways in mice and ultimately humans. The team is optimistic that recent advancements, such as lipid nanoparticles that can reach the lungs in mice, will expedite the translation of this approach to clinical settings.

This breakthrough in gene-editing technology could revolutionize the treatment of cystic fibrosis, offering a more permanent solution with fewer side effects than current treatments. If successful, it could pave the way for similar approaches to treat other genetic disorders, providing hope for many patients and their families.

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