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.

Genes that are switched on or off in the human brain differ between men and women. Moreover, these differences are not uniform. They vary across cortical regions and cell types. Scientists at the National Institute of Mental Health (NIMH) and the National Institute on Aging (NIA) used single-cell sequencing and unveiled distinct gene expression patterns regulated by hormones and sex chromosomes. This detailed map of the brain’s molecular biology shows how women and men switch on and off more than 3,000 brain genes differently and expands the catalogue of X chromosome genes that escape inactivation.

Proqr Therapeutics NV has highlighted the continued progression and expansion of its early-stage pipeline of RNA editing therapies, including programs in cholestatic diseases, Hurler syndrome, metabolic dysfunction-associated steatohepatitis and Rett syndrome.

Werner syndrome results from biallelic mutations in the WRN gene on chromosome 8, leading to accelerated aging symptoms. Researchers at Sumitomo Pharma Co. Ltd. have reported the development and characterization of WRN-108, a splice-switching antisense oligonucleotide (ASO) designed to induce exon 27 skipping in WRN transcripts carrying the c.3139-1G>C mutation.

Certain cancers, such as triple-negative breast cancer, produce antibodies that, although they help fight the tumor, can cross the blood-brain barrier and alter the function of NMDA receptors (NMDAR) in the brain, which are essential for neuronal signaling. Scientists at Cold Spring Harbor Laboratory (CSHL) have identified their origin and described how this process is linked to the maturation of these antibodies, which can activate or inhibit the receptor, causing neurological and psychiatric symptoms.

Parkinson’s disease is a progressive neurodegenerative disorder best known for its motor symptoms. However, a proportion of patients also develop dementia as the condition advances. Yet the biological divide between those who experience this cognitive decline and those who do not has remained an open question. Are they different conditions or simply stages of the same disease?

Gene editing holds promise for treating neuromuscular disorders such as limb-girdle muscular dystrophy, but its clinical translation remains challenging due to a lack of complementary delivery tools for the extensive network of skeletal muscles in the human body. A team at University of Massachusetts Chan Medical School compared editing outcomes mediated by either Cas9 mRNA and RNP delivery to skeletal muscle via local injection in the context of the previously described selective organ targeting (SORT) lipid nanoparticles (LNPs) platform.

Researchers from Arthex Biotech SL, the University of Valencia (Spain) and collaborators sought to address the lack of optimized microRNA (miRNA)-targeting antisense oligonucleotides (anti-miRs) for upregulating MBNL1 in myotonic dystrophy.