UCLA researchers have developed a new gene-editing method using lipid nanoparticles to insert a healthy gene into human airway cells. This approach restored important biological function in a laboratory model of cystic fibrosis, offering a potential new direction for treating inherited lung diseases regardless of the specific genetic mutation.
The study, published in Advanced Functional Materials, demonstrated that lipid nanoparticles—commonly used in mRNA vaccine delivery—can be modified to transport complex genetic material needed for accurate insertion of a large gene into the genome without relying on viral vectors.
Cystic fibrosis is caused by mutations in the CFTR gene, which affects chloride and water movement across airway cells. When this channel does not work correctly, it results in thick mucus that can lead to chronic infections and lung damage. While current drugs called CFTR modulators help many patients, about 10% do not produce enough CFTR protein for these treatments to be effective.
"For those patients, gene therapy isn't just an improvement - it's really the only option," said Dr. Brigitte Gomperts, co-author of the study and associate director of translational research at the stem cell center. "You have to give the cell the ability to make the protein in the first place."
With over 1,700 known mutations causing cystic fibrosis, researchers aimed for a universal strategy that could correct any error with one edit rather than addressing each mutation separately.
Traditional experimental therapies often use viral vectors to deliver genes but face limitations such as manufacturing complexity and immune response issues after repeated doses. The UCLA team instead engineered lipid nanoparticles to carry three components: CRISPR tools for cutting DNA at precise spots, guide molecules for targeting specific genomic locations, and a DNA template containing a full copy of the healthy CFTR gene.
"Getting all of that into a single particle - especially a gene as large as CFTR - is something that hadn't been shown before," said Ruth Foley, first author and recent Ph.D. graduate from UCLA's Jonas lab. "If you can solve the 'big gene' problem, it opens the door for a lot of other diseases as well."
Testing on lab-grown human airway cells with severe cystic fibrosis mutations showed successful delivery of healthy CFTR genes into approximately 3–4% of cells. Despite this small proportion, normal CFTR channel function was restored in 88% to 100% of cells tested.
Researchers attribute this outcome not only to where they inserted the gene but also how it was designed. The replacement gene was optimized for high protein production within cells—a technique developed with collaborators from Dr. Donald Kohn's lab at UCLA—so even few corrected cells could significantly improve overall function.
Unlike messenger RNA therapies that require repeated dosing, this method inserts corrected genes directly into cell genomes. This may allow long-term production of functional proteins by both treated cells and their descendants.
However, achieving lasting benefit will depend on reaching airway stem cells deep within lung tissue because these regenerate airways throughout life. "These stem cells are long-lived and constantly regenerate the airway," said Gomperts. "If you can correct them, you could, in theory, have a lasting source of healthy cells."
Delivering treatment past natural barriers—including thick mucus present in cystic fibrosis patients—remains challenging. "This paper is a proof of concept," said Jonas, assistant professor at UCLA's medical school and member of California NanoSystems Institute. "It shows that we can package and deliver the right genetic cargo. The next challenge is getting it to the right cells in the body."
Lipid nanoparticle systems are modular and do not use viral parts; this flexibility may make future therapies easier to scale up or adapt for other conditions involving large genes with multiple possible mutations.
"This kind of platform gives you room to iterate," Foley said. "If you need to re-dose or adapt the cargo for a different disease, you're not starting from scratch."
Researchers believe their approach could eventually apply beyond cystic fibrosis to other genetic lung diseases or conditions affecting different tissues where large genes play a role.
"For patients who currently have no effective treatments," Gomperts said, "this kind of work represents hope - not because it will be ready tomorrow, but because it shows a path forward."
Additional contributors included Paul G. Ayoub, Vrishti Sinha, Colin Juett, Alicia Sanoyca, Emily C. Duggan, Lindsay E. Lathrop, Priyanka Bhatt, Kevin Coote and Beate Illek.
The project received support from several organizations including federal agencies focused on health research as well as foundations dedicated specifically to cystic fibrosis studies.
