Therapeutic Potential of CRISPR–Cas3 Genome-Editing System for Transthyretin Amyloidosis. Credit: Institute of Medical Science, The University of Tokyo, Japan
A fresh twist on gene editing could change the future of treatment for transthyretin amyloidosis (ATTR). This progressive disease clogs the body with misfolded proteins and leads to heart failure and nerve damage.
ATTR comes in two forms: one linked to aging, the other inherited through destabilizing mutations in the TTR gene. Current RNA‑interference drugs can suppress TTR production, but they require lifelong dosing and don’t offer a cure. That’s why scientists are turning to gene editing, tools that can rewrite DNA itself.
CRISPR–Cas9 has been hailed as revolutionary, but it isn’t perfect. Its ‘molecular scissors’ can sometimes cut DNA in the wrong place, raising safety concerns.
A team led by Professor Tomoji Mashimo and Dr. Saeko Ishida at the University of Tokyo tested a different approach: CRISPR–Cas3, a system that doesn’t just snip DNA; it shreds long stretches of it in one direction.
“Genome editing holds the unique potential to correct the inherited disease-associated genetic abnormalities. We wanted to see if the CRISPR–Cas3 system can be developed as an efficient therapeutic genome-editing tool,” Mashimo explained.
Using a mouse model of ATTR and a lipid nanoparticle (LNP) delivery system, the researchers achieved striking results: 59% editing at the TTR locus in lab experiments, 48% hepatic editing in mice after a single treatment, and 80% reduction in serum TTR levels.
“Through CRISPR RNA optimization, we achieved around 59% editing at the TTR locus in our in vitro experiments. In the mouse model, a single LNP-based treatment helped us to achieve more than 48% hepatic editing and reduced serum TTR levels by 80%,” Mashimo highlighted.
Importantly, Cas3 avoided the off‑target mutations that plague Cas9, suggesting a safer path forward.
The impact goes far beyond ATTR. Genetic diseases happen because of changes in our DNA, and Cas3 can actually cut out the harmful parts for good. That means it could offer lasting, one‑time treatments. Unlike RNA‑based drugs, which only ease the symptoms, Cas3 goes straight to the source of the problem.
“In the coming years, this technology can lead to clinical applications not only for ATTR, but also for other currently incurable inherited diseases,” Mashimo said.
As gene editing tools evolve, society faces profound questions: how to balance safety, accessibility, and ethics while harnessing technologies that can rewrite life itself.
The new Cas3 approach offers hope because it seems to work with precision, without the risky side effects seen in older tools. If it holds up, Cas3 could shift genetic medicine from temporary symptom control to lasting cures that tackle the problem at its source.
For patients with ATTR and other inherited conditions, that future can’t come soon enough.
Journal Reference:
- Ishida, S., Sato, Y., Chosa, K. et al. CRISPR–Cas3-based editing for targeted deletions in a mouse model of transthyretin amyloidosis. Nat Biotechnol (2026). DOI: 10.1038/s41587-025-02949-6