Introduction
A groundbreaking CRISPR gene-editing therapy has emerged as a promising, long-lasting treatment for cystic fibrosis, overcoming a significant hurdle that has stymied previous genetic therapies. This innovative approach has successfully modified DNA in difficult-to-reach lung stem cells in mice, with these modifications persisting for the animals’ entire lifespans.
The study, led by Daniel Siegwart at the University of Texas Southwestern Medical Centre, marks a significant milestone in the quest to treat cystic fibrosis, a genetic disease that causes thick mucus to accumulate in the lungs and digestive system. Previous attempts at gene therapy for cystic fibrosis faced substantial challenges, particularly in delivering therapeutic agents to the affected lung cells. The lungs’ natural defences, including mucus, have evolved to block pathogens, making it difficult for gene-editing tools to reach their target.
Siegwart and his team have tackled this problem by developing a method to deliver CRISPR components directly to the lungs via the bloodstream. The key to their success lies in the use of lipid nanoparticles, which are tiny, fat-based particles capable of transporting gene-editing tools past the immune system's barriers. While lipid nanoparticles are typically directed to the liver, Siegwart's team modified them to specifically target lung tissue.
In their latest study, eight-week-old mice were injected with these lung-targeted lipid nanoparticles carrying CRISPR gene-editing tools, along with a marker to track the edited cells. Over the course of 22 months, the researchers repeatedly analysed the mice’s lung tissues and consistently found the marker present, indicating that the gene edits had persisted throughout the animals' lifetimes.
This finding was particularly surprising because individual lung cells typically have a lifespan of just three weeks. However, the treatment's ability to target lung stem cells, responsible for generating new cells—means that the gene-editing effects are continuously replenished, creating a lasting pool of healthy, edited cells.
To further validate their approach, the researchers tested the therapy on cells from people with cystic fibrosis carrying a specific genetic mutation. The CRISPR system embedded in the nanoparticles successfully corrected the mutation in these human cells. The team then tested the treatment on genetically modified mice carrying the same cystic fibrosis mutation. Within just 10 days, the treatment had corrected the mutation in 50% of the mice’s lung stem cells.
Experts in the field, such as Marianne Carlon and Mattijs Bulcaen from KU Leuven in Belgium, have praised this innovative method for achieving what previous efforts could not. In a commentary on the study, they noted that more than 27 clinical trials for cystic fibrosis gene therapy have failed to overcome the barrier of the airway epithelium, making this new approach a significant achievement.
If this therapy is approved for human trials, it would be administered to adults and specifically target lung cells, potentially offering cystic fibrosis patients lung function comparable to healthy individuals. The benefits could last as long as the lung cells themselves, potentially providing years, or even a lifetime, of improved health.
“Genome correction has the potential to generate years or perhaps a lifetime of benefit, which could dramatically improve quality of life,” Siegwart emphasized.
This groundbreaking research, published in the journal Science, offers new hope for cystic fibrosis patients, potentially revolutionizing treatment for this debilitating genetic disorder.
References
- Siegwart, D., et al. Science, 2024. DOI: 10.1126/science.adk9428.
- University of Texas Southwestern Medical Centre Research News, 2024.
- Carlon, M., & Bulcaen, M. Commentary on CRISPR Lung Therapy, 2024.