CRISPR to the rescue of trisomy 21

Leer en Español

---

Down syndrome is a genetic condition caused by the presence of an extra chromosome, chromosome 21. In February 2025, a study published in the journal PNAS by researcher R. Hashizume and his team opened a new door in Down syndrome research. The study explored the possibility of removing the extra chromosome responsible for trisomy 21, thereby restoring the normal number of chromosomes in cells.

How was the study conducted?

The team in Japan used skin cells obtained from a pediatric patient with trisomy 21. Through a meticulous process, they identified specific DNA sequences (base pair repeats) that allowed them to distinguish each of the three chromosome 21s present in the cells. This was crucial for precisely selecting which of the three chromosomes to eliminate, avoiding damage to the other two and maintaining the cell’s genetic integrity.

Using CRISPR-Cas9 gene-editing technology, the researchers successfully removed the extra chromosome 21 in 13% of the analyzed cells. This percentage was obtained by dividing the number of cells that lost the extra chromosome by the total number of cells studied. In other words, approximately a quarter of the treated cells regained their normal chromosome count.

Additional Results

The method used to select which chromosome to remove improved cell viability and functionality. Cells with targeted deletion showed a 57% survival rate, 44.3% higher compared to those where chromosome removal was random. Additionally, the extra chromosome was eliminated not only in differentiated cells, such as skin cells, but also in undifferentiated cells, such as neuronal cells.

With a karyotype (an image of a cell’s chromosomes), the researchers confirmed that the patient’s original cells had three chromosome 21s (47, XY, +21), while the CRISPR-Cas9-treated cells showed a mix: some retained trisomy (47, XY, +21), and others regained the normal chromosome count (46, XY).

One of the most relevant findings was that in cells where the extra chromosome was successfully removed, genes related to brain development and function showed higher expression compared to cells that still had trisomy. On the other hand, genes associated with metabolic stress were expressed less in the rescued cells, which also correlated with reduced oxidative stress production. These results are especially significant as they reflect clinical aspects observed in patients with Down syndrome.

Limitations

Although the results are encouraging, it is important to note that this study was conducted in an in vitro cell model, meaning it was not tested in complete tissues or living organisms. Additionally, the removal of the extra chromosome was not complete in all cells, and in some cases, only parts of the chromosome were eliminated, leading to genomic alterations and mutations. Neuronal or glial cells, which are crucial for understanding the impact of Down syndrome on the brain, were also not analyzed.

What does this mean for the future?

This study represents the first time that the extra chromosome in trisomy 21 cells has been successfully and precisely removed. This advance lays the groundwork for the development of future therapeutic interventions targeting trisomy 21. However, there is still a long way to go before these findings can be translated into clinical applications. Further research is needed to improve the efficiency of extra chromosome removal, ensure the safety of the process, and evaluate its impact in more complex models, such as tissues and whole organisms.

Conclusion

In summary, this work represents a significant advance in the understanding and potential management of Down syndrome. While not an immediate solution, it opens a window of hope for future gene therapies that could improve the quality of life for individuals with this condition.

Reference:

Hashizume, R. et al. Trisomic rescue via allele-specific multiple chromosome cleavage using CRISPR-Cas9 in trisomy 21 cells. PNAS Nexus 4, pgaf022 (2025)

---