Researchers have identified a gene therapy for individuals who have cystic fibrosis (CF) caused by the 1717-1G>A mutation. The groundbreaking discovery opens the door for a permanent cure for patients with the difficult-to-treat condition type (about 10% of the CF population).
The mRNA-based precision strategy is detailed in the paper, “Functional Correction of the Untreatable CFTR 1717-1G>a Mutation Through mRNA- And sgRNA-Optimized Base Editing,” published in Science Translational Medicine.
Investigators from the University of Trento in Italy, including co-corresponding authors Anna Cereseto, PhD, and Alessandro Umbach PhD, led the study. Individuals with this severe type of CF do not produce the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The therapeutic approach uses genome editing technology (CRISPR) to repair the DNA mutation.
The researchers used the ABE9 base editor and modified CRISPR-Cas9 tool to manipulate the spliced gene in a human embryonic kidney cellular model, obtaining 30% editing of target DNA with minimal off-target effects. They also performed genetic repair in patient-derived airway epithelial cells and intestinal organoids for an overall editing proficiency of 13%.
Specifically, the lab group substituted pathogenic adenine in the defective gene with guanine. Repairing the mutation restored production of the CFTR protein, which regulates gas exchange, mucus levels and immune defense in the lungs.
“Although in vivo efficacy remains to be tested, given that only 10% CFTR expression may be enough for recovery, this approach could hold promise for the treatment of people with CF carrying the CFTR 1717-1G>A mutation,” wrote Melissa L. Norton, MD, senior editor of Science Translational Medicine.
