Novel Method Expands Gene Editing to Correct Multiple Mutations

Scientists at The University of Texas at Austin have engineered a gene-editing method that addresses a major limitation in treating genetic disorders involving multiple mutations. Conditions like cystic fibrosis, hemophilia, and Tay-Sachs disease often present with diverse mutational profiles across patients, making one-size-fits-all therapies difficult to design. The new approach leverages retrons—genetic elements from bacteria that defend against viruses—to enable the simultaneous correction of numerous disease-causing mutations within a single stretch of DNA. 

This technique allows for the replacement of large defective genomic segments with healthy sequences, meaning the same retron-based system can treat individuals with different mutation combinations in the targeted region. It achieved a correction rate of approximately 30% in mammalian cells, a significant improvement over previous retron methods that succeeded in only about 1.5% of targeted cells. The team also demonstrated its functionality in zebrafish embryos, successfully correcting mutations linked to scoliosis—a first for retron editing in vertebrates.

The method’s delivery mechanism uses RNA encapsulated in lipid nanoparticles, which are designed to overcome challenges associated with conventional gene-editing delivery systems. This feature enhances its potential for clinical application, particularly in diseases where precision and broad targeting are critical.

Led by Jesse Buffington and Ilya Finkelstein, the research aims to expand access to gene therapy. “A lot of the existing gene-editing methods are restricted to one or two mutations, which leaves a lot of people behind,” said Buffington, first author of the study published in Nature Biotechnology. “My hope, and what drives me, is to develop a gene-editing technology that’s much more inclusive of people who might have more unique disease-causing mutations.”

The team is now focusing on cystic fibrosis, a condition driven by over a thousand possible mutations in the CFTR gene. With support from Emily’s Entourage and the Welch Foundation, they are working to replace faulty sections of the gene in patient-derived airway cells. Finkelstein emphasized the broader goal: “We want to democratize gene therapy by creating off-the-shelf tools that can cure a large group of patients in one shot.”