Researchers achieve a breakthrough in correcting a rare metabolic condition in mice using a safer, temporary gene-editing method.
A new gene-editing strategy is showing great promise for treating phenylketonuria (PKU), a rare but serious genetic liver disorder. Scientists from the University of Zurich have developed a method that successfully corrected the disease-causing mutation in mice without permanently altering their DNA machinery — potentially paving the way for safer genetic therapies in humans.
What is PKU?
PKU is a genetic disorder where the body cannot properly break down an amino acid called phenylalanine. Without treatment, high levels of phenylalanine build up in the blood, which can lead to severe intellectual disability, seizures, and other complications. Current treatments require a strict diet and regular enzyme therapy, which can be difficult for patients to maintain.
A Smarter, Safer Way to Edit Genes
The team used a cutting-edge technology called prime editing to correct the specific mutation responsible for PKU in mice. Unlike earlier gene-editing methods, which can leave permanent changes and unwanted side effects, this new approach temporarily introduces editing tools into the body using lipid nanoparticles (LNPs) — tiny, fat-like molecules that can safely deliver gene-editing instructions to liver cells.
Two key components were delivered:
- Prime editing mRNA, which contains the instructions for a precision editing enzyme.
- pegRNA, a guide molecule that directs the enzyme to the exact mutation needing repair.
In some experiments, the guide was delivered using a virus (AAV) for better stability. In others, both components were delivered via LNPs — a method similar to how mRNA COVID-19 vaccines work.
The Results: Lower Disease Markers, No Harmful Side Effects
The results were impressive. In mice with PKU, this method:
- Achieved correction rates of up to 20.7% in liver cells.
- Lowered harmful phenylalanine levels in the blood to safe levels — below 360 µmol/l, the target for children and pregnant women.
- Showed no significant off-target effects or liver damage.
Notably, the researchers also tested a newer, more powerful editor called PE7, which improved results even further when combined with chemically protected guide RNAs.
Why This Matters
Traditional gene therapy often uses permanent viral tools to deliver genes, which can raise safety concerns due to immune reactions or long-term changes. This study proves that transient delivery — where the editing tools disappear from the body shortly after doing their job — can still achieve lasting genetic corrections.
“This is a major step toward treating inherited liver diseases more safely,” said Dr. Gerald Schwank, lead researcher. “The technology could be adapted to target other mutations in the future, offering hope for many patients with genetic disorders.”
What’s Next?
The study was conducted in mice, and more research is needed to test its safety and effectiveness in humans. However, the authors believe this method could soon lead to clinical trials for PKU and similar liver-based genetic conditions.
Takeaway: Scientists have developed a highly effective, temporary gene-editing technique that can correct genetic liver disease in mice, offering hope for safer and more scalable treatments for disorders like PKU.
References
- Blau, Nenad, et al. "Phenylketonuria." The Lancet, vol. 376, no. 9750, 2010, pp. 1417–1427. https://doi.org/10.1016/S0140-6736(10)60961-0.
- Böck, Desirée et al. “In vivo prime editing of a metabolic liver disease in mice.” Science translational medicine vol. 14,636 (2022): eabl9238. doi:10.1126/scitranslmed.abl9238
- Anzalone, Andrew V., et al. "Search-and-replace genome editing without double-strand breaks or donor DNA." Nature, vol. 576, no. 7785, 2019, pp. 149–157. https://doi.org/10.1038/s41586-019-1711-4.
- Musunuru, Kiran, et al. "In Vivo CRISPR Base Editing of PCSK9 Durably Lowers Cholesterol in Primates." Nature, vol. 593, 2021, pp. 429–434. https://doi.org/10.1038/s41586-021-03534-y.
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