Lipid nanoparticle gene editing restored up to 100% of normal CFTR function in lab tests
A lipid nanoparticle gene-editing approach inserted a full healthy CFTR gene into human airway cells and restored 88% to 100% of normal CFTR function in lab tests. The nonviral strategy is intended as a mutation-agnostic path for cystic fibrosis.
Researchers developed a nonviral gene-editing strategy for cystic fibrosis that uses lipid nanoparticles to insert a full, healthy copy of the CFTR gene into human airway cells. In laboratory tests, the treatment inserted a healthy CFTR gene into approximately 3% to 4% of cells and restored between 88% and 100% of normal CFTR channel function across the cell population.
The study, published in Advanced Functional Materials, showed that lipid nanoparticles can be engineered to carry three components of the gene-editing machinery: CRISPR to cut DNA at a precise location, guide molecules to target the correct genomic site, and a DNA template encoding a full, functional copy of the CFTR gene. The researchers said getting all of that into a single particle, especially a gene as large as CFTR, had not been shown before.
The researchers tested the system in lab-grown human airway cells carrying a severe cystic fibrosis mutation that does not respond to existing drugs. The replacement CFTR gene was designed to maximize protein production once it entered the cell, enabling even a small number of corrected cells to have an outsized effect.
Cystic fibrosis is caused by mutations in the CFTR gene, which encodes a channel that helps move chloride and water across the surface of airway cells. Although CFTR modulators have transformed care for many people with cystic fibrosis, about 10% of patients produce little or no CFTR protein at all, leaving nothing for those drugs to act on.
Because there are more than 1,700 mutations associated with cystic fibrosis, the team aimed to develop a universal, mutation-agnostic gene therapy. By inserting a therapeutic gene directly into the genome, the strategy may allow cells to continue producing working CFTR protein over time, with no need of redosing.
The researchers said the next challenge is delivering the therapy to airway stem cells located deep within the lung’s protective lining, which continually renew and repair lung tissue. They also identified the thick mucus in the airways that is a hallmark of cystic fibrosis as another obstacle to reaching those cells.