Alterman, J.F. et al. Nat. Biotechnol. 37, 884–894 (2019)

Technologies to modulate gene expression in the central nervous system (CNS) include adeno-associated virus, antisense oligonucleotides, and siRNAs. A variety of chemical modification patterns have been explored to improve siRNA delivery into the brain, which remains challenging. In a new study, a team of investigators from the University of Massachusetts Medical School developed a divalent chemical scaffold of siRNA (di-siRNA) that allows widespread distribution of siRNA and sustained gene silencing in the CNS of mice and nonhuman primates after injection into the cerebrospinal fluid. In addition, in a mouse model of Huntington’s disease, the delivery of di-siRNAs targeting HTT downregulated huntingtin expression throughout the brain. This siRNA design could be used in future siRNA-based strategies for the treatment of neurological disorders.