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Researchers affiliated with Mass General Brigham and Beth Israel Deaconess Medical Center have introduced STITCHR, an innovative gene editing technology capable of inserting therapeutic genes at precise points within the genome without inducing unintended mutations. This tool utilizes an all-RNA approach, representing a significant advancement over more traditional methods that rely on both RNA and DNA, thereby simplifying delivery logistics considerably. By facilitating the insertion of entire genes, STITCHR presents a streamlined solution that addresses some limitations associated with CRISPR gene editing, which primarily focuses on correcting specific mutations. The findings of this study are detailed in Nature.
“While CRISPR has dramatically changed the landscape of gene editing, it does have its drawbacks. Specifically, CRISPR cannot target every genomic site, nor can it address all the mutations linked to conditions such as cystic fibrosis,” commented co-senior author Omar Abudayyeh, PhD, a researcher at the Gene and Cell Therapy Institute (GCTI) at Mass General Brigham and the Engineering in Medicine Division at Brigham and Women’s Hospital (BWH). He further explained, “When establishing our lab, we aimed to determine how we could insert larger gene fragments—or even entire genes—to replace defective ones. This capability would enable us to tackle every mutation associated with a particular disease using just one gene editing construct.”
STITCHR leverages the unique properties of enzymes derived from retrotransposons, genetic elements that exist in all eukaryotic organisms, including animals, fungi, and plants. Commonly referred to as “jumping genes” due to their ability to relocate within the genome, these elements provided inspiration for the researchers. They identified that the copy-and-paste mechanism utilized by retrotransposons could be adapted for precise gene editing.
The research team, led by Christopher Fell, PhD, also of the GCTI and BWH Division of Engineering in Medicine, employed a computational methodology to examine a myriad of retrotransposons, searching for candidates suitable for reprogramming. Eventually, they refined their results down to a specific candidate and integrated it with a nickase enzyme from the CRISPR system, culminating in the creation of the STITCHR platform.
Looking ahead, the team intends to further enhance the efficiency of this gene editing system and is actively working towards its application in clinical settings.
“By investigating fundamental biological processes in our cells, we can derive new tools and methods. This research can broaden our capabilities in cell engineering and pave the way for novel medications and therapies targeting both rare and widespread diseases,” stated co-corresponding author Jonathan Gootenberg, PhD, affiliated with the Center for Virology and Vaccine Research at BIDMC, the Gene and Cell Therapy Institute at Mass General Brigham, and a faculty member at Harvard Medical School.
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