Japanese researchers at Mie University, led by Dr. Ryotaro Hashizume, have successfully demonstrated that it’s possible to delete the extra copy of chromosome 21 that causes Down syndrome using allele-specific CRISPR-Cas9 editing in cell-based experiments. This represents the first proof-of-concept showing chromosomal correction at the root of the disorder. Medical Xpress
The Allele‑Specific Trisomic Rescue Method
Using a precise editing strategy, the team engineered CRISPR guide RNAs targeting unique DNA sequences on the extra (third) chromosome in trisomy 21 cells. This precise targeting ensures only the redundant copy is cut, while retaining one maternal and one paternal chromosome per cell. Efficiency reached up to 30–37% correction in both induced pluripotent stem cells and differentiated skin fibroblasts.
To boost effectiveness, the researchers temporarily knocked down DNA repair genes LIG4 and POLQ, improving chromosome removal rates.
Restoring Normal Gene Expression and Cell Health
After trisomy correction, treated cells displayed normalized gene expression profiles, especially for genes critical to nervous system development. The corrected cells showed improved proliferation, reduced levels of reactive oxygen species, and restored mitochondrial function—signs of healthier cellular states.
Far From Clinical Use: Key Limitations
Despite its promise, the method remains limited to in vitro research. Off-target edits—affecting healthy chromosomes—remain a concern, and no animal or human studies have been conducted yet. Researchers stress that in vivo applications will need months or years of further refinement, delivery mechanisms, and safety evaluations.
Ethical and Practical Implications
This approach marks a paradigm shift: instead of treating downstream symptoms, it addresses the genetic cause of Down syndrome at a fundamental level. However, profound ethical concerns persist. Advocacy groups caution against equating genetic variation with defects, emphasizing individual dignity and the risk of unintended consequences.
What Lies Ahead
Further studies are needed to:
- Optimize allele-specific editing to minimize off-target effects
- Develop reliable delivery systems for neurons and glial cells
- Ensure long-term stability and safety in tissue models and animal systems
Though not yet viable for medical use, the breakthrough sets the groundwork for future regenerative therapies targeting chromosomal disorders, not just single-gene conditions.
Summary
Japanese researchers have taken a groundbreaking step by demonstrating that CRISPR-Cas9 can precisely remove the extra chromosome responsible for Down syndrome in human cells. By restoring normal gene expression and improving cell function in both stem and mature cells, they have shown what may become a transformational approach—though clinical application remains distant. Ethical safeguards and technical improvements will be critical before any in vivo use can be considered.
