STITCHR: New gene editing technology advances whole-gene replacement therapy
Researchers have developed a novel RNA-based gene editing system capable of inserting entire therapeutic genes, addressing limitations of current CRISPR technology for diseases with multiple mutations.
A team of investigators from Mass General Brigham and Beth Israel Deaconess Medical Center has unveiled a promising new gene editing tool that could transform treatment approaches for genetic diseases. Published in Nature on April 9, 2025, the technology named STITCHR offers a complete RNA-based system for precise gene insertion without unwanted mutations.
How STITCHR works
STITCHR harnesses enzymes from retrotransposons—genetic elements nicknamed “jumping genes” for their ability to move throughout the genome. The researchers repurposed these elements’ natural copy-and-paste mechanisms to create a system that can insert therapeutic genes at specific locations.
“CRISPR has revolutionised how we think about gene editing, but it has limitations. CRISPR can’t target every location in the genome, and it can’t fix the thousands of mutations present in diseases like cystic fibrosis,” explained co-senior author Omar Abudayyeh, PhD, an investigator at the Gene and Cell Therapy Institute at Mass General Brigham.
The team, led by Christopher Fell, PhD, used computational screening to identify promising retrotransposons that could be reprogrammed. They then combined their lead candidate with a CRISPR nickase enzyme to create the complete STITCHR system, enabling seamless gene insertion.
Advantages over current gene editing technologies
STITCHR represents a significant advance over existing gene editing approaches in several key ways:
- Complete RNA formulation – Unlike traditional systems requiring both RNA and DNA, STITCHR can be formulated entirely as RNA, simplifying delivery logistics considerably.
- Whole-gene replacement – The system can insert entire genes, creating a “one-and-done” approach that addresses multiple mutations simultaneously.
- Targeting precision – STITCHR can insert genes at specific genomic locations without causing unwanted mutations elsewhere.
“When we started our lab, one of the big things we wanted to figure out was how to insert large pieces of genes, or even entire genes, to replace faulty ones. This would allow us to target every mutation for a disease with a single gene editing construct,” said Abudayyeh.
Translational potential and future directions
The researchers are now focused on enhancing the system’s efficiency and working towards clinical applications. The technology holds particular promise for diseases characterised by multiple genetic mutations, where correcting individual variants would be impractical.
“By studying basic biology in our cells, we can find inspiration for new tools. These can expand our cell engineering capabilities and lead to creation of new medicines and therapies for both rare and common diseases,” noted co-corresponding author Jonathan Gootenberg, PhD, from the Center for Virology and Vaccine Research at BIDMC.
A patent application related to STITCHR has been filed, and both Gootenberg and Abudayyeh are co-founders of Terrain Biosciences, suggesting potential commercial development pathways.
Reference
Fell, C., Tagliaferri, D., Jiang, K., et. al. (2025). Reprogramming site-specific retrotransposon activity to new DNA sites. Nature. https://doi.org/10.1038/s41586-025-08877-4
