Gene-editing breakthrough offers hope for cystic fibrosis treatment
Researchers have developed a novel gene-editing approach that efficiently corrects the most common cystic fibrosis mutation, potentially paving the way for a one-time, permanent treatment with fewer side effects than current therapies.
Cystic fibrosis treatment may be on the cusp of a revolutionary breakthrough, thanks to a new gene-editing technique developed by researchers at the Broad Institute of MIT and Harvard and the University of Iowa. The study, published in Nature Biomedical Engineering [1], demonstrates a highly efficient method for correcting the most common genetic mutation responsible for cystic fibrosis, offering hope for a more effective and less burdensome treatment option for patients.
The challenge of treating cystic fibrosis
Cystic fibrosis, one of the most prevalent genetic disorders, affects thousands of individuals worldwide. The condition is characterised by the build-up of thick mucus in the lungs and other organs, leading to breathing difficulties and increased susceptibility to infections. While recent advancements in treatment, such as the three-drug cocktail Trikafta, have significantly improved patient outcomes, these therapies come with drawbacks including potential side effects and the need for lifelong daily administration at a substantial cost.
A precise gene-editing solution
The research team, led by David Liu, the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad Institute, has developed a gene-editing approach that targets the most common cystic fibrosis mutation. This mutation, found in 85% of patients, involves a three base-pair CTT deletion in the CFTR gene, which causes the ion channel protein to misfold and degrade.
Using a technique called prime editing, the researchers were able to make precise insertions, deletions, and substitutions in the genome with minimal unwanted effects. This method, developed in Liu’s lab in 2019, offers greater flexibility and control compared to traditional gene-editing approaches.
“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,” said Liu, the senior author of the study.
Optimising the editing process
To achieve high efficiency in correcting the CFTR mutation, the research team combined six different enhancements to the prime editing technology. These improvements included:
- Refining the prime editing guide RNAs that direct the editing process
- Modifying the prime editor protein itself
- Making the target site more accessible
The result was a remarkable increase in editing efficiency, with about 60% of CTT deletions corrected in human lung cells and approximately 25% in cells taken directly from patient lungs. This represents a significant improvement over previous methods, which corrected less than 1% of the mutation in cells.
Importantly, the new approach also generated 3.5 times fewer unwanted insertions and deletions per edit compared to previous methods using the Cas9 nuclease enzyme.
Potential for a one-time treatment
The successful correction of the CFTR mutation in human cells offers the tantalising possibility of a one-time, permanent treatment for cystic fibrosis. This approach could potentially eliminate the need for daily medication regimens and reduce the risk of side effects associated with current treatments.
“Developing a strategy to efficiently correct this challenging mutation also provided a blueprint for optimising prime editing to precisely correct other mutations that cause devastating disorders,” Liu added, highlighting the broader implications of this research.
Next steps and future challenges
While the results are promising, there are still hurdles to overcome before this gene-editing approach can be translated into a clinical treatment. The researchers now face the task of developing methods to package and deliver the prime editing machinery to the airways in animal models and, eventually, human patients.
Recent advancements in delivery systems, such as lipid nanoparticles that can reach the lungs in mice, offer hope for expediting the translation of this approach to clinical applications.
Implications for genetic medicine
The success of this gene-editing approach in correcting the most common cystic fibrosis mutation represents a significant milestone in the field of genetic medicine. If further developed and proven safe and effective in clinical trials, this technique could revolutionise the treatment of cystic fibrosis and potentially other genetic disorders.
By offering a one-time treatment option that addresses the root cause of the disease, this approach could dramatically improve the quality of life for patients with cystic fibrosis, reducing their dependence on daily medications and mitigating the risk of long-term side effects.
As researchers continue to refine and optimise gene-editing technologies, the prospect of precise, permanent corrections for genetic disorders moves ever closer to reality. The work of Liu and his colleagues represents a crucial step forward in this journey, offering renewed hope to patients and families affected by cystic fibrosis and other genetic conditions.
Reference:
- Sousa, A. A., Hemez, C., et al. (2024). Systematic optimization of prime editing for the efficient functional correction of CFTR F508del in human airway epithelial cells. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-024-01233-3
