A modified version of CRISPR-Cas9 has enabled, for the first time, the efficient integration of a large transgene capable of inactivating entire chromosomes into one of the three copies of chromosome 21 in Down syndrome-derived cells. The goal is to silence the extra copy to limit the gene-dosage imbalance that drives many features of trisomy 21. Researchers at Beth Israel Deaconess Medical Center turned to XIST, the long noncoding RNA responsible for the natural silencing of the X chromosome in females. Using this strategy, they achieved integration efficiencies of 20% to 40% and a partial reduction in the overexpression of chromosome 21 genes.