A team of Japanese scientists has achieved a landmark breakthrough: using CRISPR‑Cas9, they successfully deleted the extra copy of chromosome 21 responsible for Down syndrome in human cells.
The study, published on February 18, 2025 in PNAS Nexus, outlines a precise "trisomic rescue" method that restores normal gene expression and improves cellular function in both stem cells and skin fibroblasts
Lead researcher Ryotaro Hashizume of Mie University and his colleagues used allele‑specific targeting, designing CRISPR guides that cut only the extra chromosome copy, ensuring one chromosome from each parent remains intact.
They achieved removal rates of about 13 percent, which increased to roughly 30 percent when DNA repair mechanisms were temporarily suppressed.
Allele‑Specific Cleavage
Previous gene‑editing efforts did not discriminate between three homologous copies of chromosome 21. This group, however, developed a technique to phase haplotypes and identify unique allele‑specific CRISPR targets.
By extracting over 15,000 recognition sequences specific to the duplicated “M2 allele,” they achieved controlled removal, minimizing off‑target damage.
Using multiple simultaneous CRISPR cuts designated AS ×13 and temporarily knocking down genes involved in DNA repair (LIG4 and POLQ), the researchers raised the efficiency of trisomic rescue significantly.
Fluorescence in situ hybridization confirmed the removal of the extra chromosome and ruled out unintended chromosomal gains.
Positive Impact on Cell Behavior
Following chromosome removal, both induced pluripotent stem cells and differentiated fibroblasts displayed restored gene expression patterns and enhanced cellular phenotypes.
Specifically, treated cells showed increased activity in genes tied to nervous system development and reduced expression of metabolic‑stress genes, aligning with improved mitochondrial function and faster proliferation.
In fibroblasts, the trisomic correction boosted cell growth, reduced doubling time, and decreased reactive oxygen species, all key indicators of healthier cells.
Gene ontology analyses further confirmed that cellular behavior moved closer to typical disomy patterns, although results for downregulated genes require cautious interpretation.
Progress and Limitations
The study’s authors acknowledge this remains an in vitro, proof‑of‑concept advance. The approach is not yet ready for use in living organisms.
Risks persist, notably, potential unintended edits to the remaining chromosomes and the technical challenge of delivering precise editing machinery to mature brain cells or stem cells in vivo.
Nonetheless, Hashizume and his team emphasize that their allele‑specific method could pave the way for more advanced interventions targeting neurons and glial cells, potentially opening pathways for therapies against trisomy 21 and other chromosomal disorders.
Ethical and Clinical Considerations
As a cellular intervention, this research is a remarkable technical feat, but it also raises ethical and safety considerations.
Because CRISPR-mediated double-strand breaks could harm non-target genetic material, further refinement is needed to reduce off-target effects. Clinical translation would require proof of safety, stability of corrections, and reliable delivery systems, especially for neural tissues.
Implications for Down Syndrome Treatment
Down syndrome (trisomy 21) is the most common chromosomal disorder, affecting about 1 in 700 live births.
It typically causes cognitive impairment, characteristic physical traits, and an increased risk of health issues such as heart defects, leukemia, and Alzheimer’s-related dementia.
While current treatments focus on supportive care like speech, occupational, or physical therapy, none address the root genetic cause.
This allele-specific trisomic rescue method marks a paradigm shift: rather than modulating gene activity, it eliminates the extra chromosome entirely. In doing so, it rebalances genetic dosage, opening a new frontier in treating chromosomal disorders at their source.
That said, researchers emphasize there is still a long road ahead, especially for translating in vitro success into in vivo safety and clinical viability.
A Groundbreaking Discovery
The publication in PNAS Nexus of this Japanese-led research marks a historic technical milestone. It proves that CRISPR‑Cas9 can, in principle, eliminate an entire human chromosome copy with a high degree of precision and measurable functional recovery in cells.
Though still at the experimental stage, the work provides a blueprint for future strategies aimed at genetic disorders caused by chromosomal anomalies.
Key next steps will include improving targeting accuracy, developing delivery systems for mature tissues, conducting long-term safety evaluations, and navigating the ethical implications of germline or somatic editing.
For now, the study stands as a beacon of innovation, a proof of concept that may one day reshape how Down syndrome and similar conditions are addressed at their genetic roots.
