CRISPR/Cas3 genome editing shows promise in treating protein misfolding disease

A new genome editing approach has been shown to safely and efficiently remove the source of transthyretin amyloidosis (ATTR) in mice, demonstrating greater therapeutic opportunities for genome editing.

Researchers from the University of Tokyo, Japan, showed that the mutated transthyretin (TTR) gene, responsible for ATTR, could be removed using CRISPR/Cas3 genome editing which, in comparison to the widely used CRISPR/Cas9 approach, causes fewer off-target effects. These results, published in the journal Nature Biotechnology, may point towards a safer and more accurate method for genome editing.

'Genome editing holds the unique potential to correct the inherited disease-associated genetic abnormalities [resulting in ATTR],' said Professor Tomoji Mashimo, who is corresponding author of the study. He added, 'We wanted to see if the CRISPR/Cas3 system can be developed as an efficient therapeutic genome-editing tool.'

ATTR is a progressive disease caused by misfolded transthyretin (TTR) proteins, which clump together, leading to dysfunction in organs such as the heart and nervous system. Inherited mutations in the TTR gene can cause this misfolding, and treatments which limit TTR production have shown some therapeutic potential. However, current treatments are not curative and require long-term application.

While CRISPR/Cas9 could be used to remove the mutated gene (see BioNews 1135 and 1167), preventing the need for ongoing treatment, its off-target effects make it riskier as a therapeutic option (see BioNews 1313). The Cas3-based approach, which involves a cascade of many proteins, generates larger-scale, unidirectional deletions instead of specific double-strand breaks, which the researchers showed decreases the volume of off-target effects.

Professor Mashimo added, 'In the coming years, this technology can lead to clinical applications not only for [ATTR], but also for other currently incurable inherited diseases.'

While this study focused on mouse models and human cell lines only, it is still hoped that these results could offer more confidence in genetic therapies, with eventual application for human patients.