Good news!
P.S. Google Scholar and Semantic Scholar (see screen print below) do not yet list this research paper published on 4/13/2026 as of writing this blog. This paper was published in the prestigious PNAS!
"Scientists have taken an important step toward a gene therapy that could one day turn off the extra genetic material that causes Down syndrome (DS). Down syndrome is a genetic condition caused by an extra chromosome 21 (and consequently hundreds of triplicate genes) that leads to developmental and neurological issues. ...
The team used a modified version of the gene-editing technique CRISPR/Cas9 ... to insert the XIST gene into the extra chromosome 21 to silence it.
They tested their technique in the lab using human stem cells that contained an extra chromosome 21. After running several experiments, the team found that CRISPR was effective at pasting the XIST silencing gene exactly where it needed to go. ..."
From the highlights and abstract:
"Significance
Down syndrome (DS) results from trisomy 21 and remains without a molecularly targeted therapy.
Prior work demonstrated that ectopic expression of the long noncoding RNA XIST could epigenetically silence the extra chromosome 21, but technical limitations, including low gene integration efficiency, have hindered translational progress.
Here, we present a CRISPR-based approach that markedly improves the efficiency and specificity of XIST integration into an extra copy of chromosome 21. By engineering Cas9-exonuclease fusion, designing SNP-specific sgRNAs, and enhancing donor–acceptor DNA pairing, we achieve a significant improvement in silencing efficiency. Our findings demonstrate partial transcriptional correction of trisomic gene dosage and offer a scalable, targeted platform for chromosomal therapy in DS and other aneuploidies.
Abstract
Down syndrome (DS) is one of the most common developmental human genetic disorders and is due to triplication of chromosome 21 (HSA21).
Although previous studies using epigenetic suppression of HSA21 by the long noncoding RNA XIST showed a potential for DS treatment, integration efficiency of XIST by conventional zinc finger nucleases is too low to allow for practical implementation.
Here, we report a modified CRISPR/Cas9 approach, which enhances the efficiency of XIST gene integration.
First, a codon-optimized λ-phage exonuclease (exo) was fused with Cas9 to create 5’- and 3’-end overhangs at cutting sites of donor DNA and acceptor chromosome DNA.
Second, four sgRNAs, two of which selectively targeted each the acceptor or donor DNA, were assembled tandemly into one Cas9 plasmid (PX459) to increase the Cas9-cutting efficiency and promote donor DNA integration.
Third, sgRNAs were designed by searching for unique single nucleotide polymorphism nucleotides distinct between the three HSA21 copies, as a protospacer adjacent motif site to specifically target one HSA21 copy.
Fourth, donor DNA plasmid containing XIST was modified to disable replication and inhibit transcription function and allow for inducible expression.
Our modified CRISPR method significantly enhanced the integration efficiency (20 to 40%) of long XIST gene (14 kb) into an extra chromosome 21 (HSA21), as was identified with PCR, cell cloning, immunostaining, and FISH.
RNA sequencing results showed that imbalance of gene transcription across extra HSA21 can be partially corrected by XIST gene integration. The modified CRISPR method with XIST paves a road for therapeutic treatment for DS."
A modified CRISPR/Cas9 approach in silencing the triplication in Down syndrome: A treatment path XISTs (no public access)
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