Gene editing technology can be used to correct trisomy 21 at the cellular level, paving the way for future therapeutic approaches for Down syndrome. In the future, CRISPR/Cas9-based techniques could enable more sophisticated medical interventions that help restore cellular functions and improve the quality of life of people with different genetic syndromes.
Down syndrome is a genetic condition caused by the presence of an extra copy of chromosome 21, a phenomenon known as trisomy 21. This is the most common chromosomal abnormality in humans and occurs in approximately 1 in 700 births.
Over the years, several studies have helped to better understand the clinical characteristics of the syndrome, its genetic causes and the impact of trisomy on cells.
With the advancement of science, animal models and early diagnosis techniques have also emerged that allow the condition to be identified before birth. However, one of the biggest challenges in research is still finding ways to correct the root cause of the syndrome, namely the presence of the extra chromosome.
One of the most promising approaches to solving this problem is the use of CRISPR/Cas9 technology, a revolutionary gene editing tool. This technique allows DNA to be modified with high precision, being able to insert, remove or alter small sections of genes.
Recent studies have shown that CRISPR/Cas9 can go further and even remove entire chromosomes from cells, paving the way for new therapeutic strategies for syndromes caused by aneuploidies, such as Down syndrome.
However, this approach faces significant challenges: when trying to eliminate an extra chromosome, there is a risk of removing any of the three chromosomes 21 present in the cell, without distinction. This can generate undesirable effects, since some genes on chromosome 21 have specific functions depending on which copy was inherited from the father and which was inherited from the mother.
To overcome this problem, scientists have developed a method called haplotype phasing, which allows them to precisely identify which of the three chromosomes should be removed.
However, current genetic sequencing techniques generally do not provide this information directly, requiring the development of new strategies.
In this study, researchers from Mie University Graduate School of Medicine, Japan, created a chromosome deletion system based on CRISPR/Cas9, designed to target only one specific copy of chromosome 21, without affecting the others.
The tests were performed on induced pluripotent stem (iPS) cells, which are cells derived from skin fibroblasts and have the ability to transform into different cell types.
By applying CRISPR/Cas9 to these cells, the researchers were able to selectively remove the extra chromosome, restoring a genetic condition closer to normal.
A graphical summary summarizes the approach. Credit: Editage. SciTechDaily
In addition, temporarily reducing the DNA damage response helped increase the success rate in eliminating the chromosome. The scientists also noted that this technique could be used in differentiated cells, that is, cells that have already assumed specific functions in the organism and are no longer actively dividing.
The results of this study demonstrate that gene-editing technology can be used to correct trisomy 21 at the cellular level, paving the way for future therapeutic approaches for Down syndrome.
Although challenges remain in applying this technique to humans, this research represents a significant advance in genetic medicine.
In the future, techniques based on CRISPR/Cas9 could enable more sophisticated medical interventions that help restore cellular functions and improve the quality of life of people with Down syndrome.
READ MORE:
Trisomic rescue via allele-specific multiple chromosome cleavage using CRISPR-Cas9 in trisomy 21 cells
Ryotaro Hashizume, Sachiko Wakita, Hirofumi Sawada, Shin-ichiro Takebayashi, Yasuji Kitabatake, Yoshitaka Miyagawa, Yoshifumi S Hirokawa, Hiroshi Imai and Hiroki Kurahashi,
PNAS Nexus, Volume 4, Issue 2, February 2025, pgaf022
Abstract:
Human trisomy 21, responsible for Down syndrome, is the most prevalent genetic cause of cognitive impairment and remains a key focus for prenatal and preimplantation diagnosis. However, research directed toward eliminating supernumerary chromosomes from trisomic cells is limited. The present study demonstrates that allele-specific multiple chromosome cleavage by clustered regularly interspaced palindromic repeats Cas9 can achieve trisomy rescue by eliminating the target chromosome from human trisomy 21 induced pluripotent stem cells and fibroblasts. Unlike previously reported allele-nonspecific strategies, we have developed a comprehensive allele-specific (AS) Cas9 target sequence extraction method that efficiently removes the target chromosome. The temporary knockdown of DNA damage response genes increases the chromosome loss rate, while chromosomal rescue reversibly restores gene signatures and ameliorates cellular phenotypes. Additionally, this strategy proves effective in differentiated, nondividing cells. We anticipate that an AS approach will lay the groundwork for more sophisticated medical interventions targeting trisomy 21.
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