New Tool Enhances Safety Of Crispr Gene Editing
The groundbreaking approval of CRISPR-Cas9-based gene therapy by the U.S. Food and Drug Administration has opened new doors in biomedicine, offering hope for treating conditions such as sickle cell disease, muscular dystrophy, and some cancers. However, the technique, often described as 'molecular scissors' due to its ability to cut DNA at precise locations, comes with safety concerns. These include the risk of unintended DNA breaks, known as off-target effects, which could lead to mutations in healthy genes.
In response to these challenges, researchers led by MIT's Ronald T. Raines and Harvard's Amit Choudhary have introduced an innovative method to deactivate Cas9 once its task is complete. This advancement significantly minimizes off-target effects, enhancing the clinical safety of this transformative technology. Their research was recently published in the Proceedings of the National Academy of Sciences (PNAS).
'We have engineered the first cell-permeable anti-CRISPR protein system to switch off Cas9 after successful genome editing,' explains Raines. 'This advancement enhances Cas9's precision and its value in clinical settings.'
The novel system, known as LF N -Acr/PA, utilizes a protein-based delivery mechanism to efficiently transport anti-CRISPR proteins into human cells. While natural anti-CRISPR proteins are known to inhibit Cas9, their therapeutic application has been limited due to difficulties in delivering them into cells. LF N -Acr/PA uses components derived from the anthrax toxin to overcome these barriers, allowing rapid and precise inhibition of Cas9 even at very low concentrations, thus improving genome-editing accuracy by up to 40%.
Bradley L. Pentelute, an MIT chemistry professor and expert in the anthrax delivery system, also contributed to this research. The implications of this advancement are vast, offering a safer and more controlled approach to CRISPR-Cas9 gene editing. With patent applications underway, LF N -Acr/PA promises to advance gene therapies with reduced side effects.
This research was backed by the National Institutes of Health and a Gilliam Fellowship from the Howard Hughes Medical Institute, supporting lead author and graduate student Axel O. Vera from MIT's Department of Chemistry.