Julia F Alterman, Bruno M D C Godinho, Matthew R Hassler, Chantal M Ferguson, Dimas Echeverria, Ellen Sapp, Reka A Haraszti, Andrew H Coles, Faith Conroy, Rachael Miller, Loic Roux, Paul Yan, Emily G Knox, Anton A Turanov, Robert M King, Gwladys Gernoux, Christian Mueller, Heather L Gray-Edwards, Richard P Moser, Nina C Bishop, Samer M Jaber, Matthew J Gounis, Miguel Sena-Esteves, Athma A Pai, Marian DiFiglia, Neil Aronin, Anastasia Khvorova
Sustained silencing of gene expression throughout the brain using small interfering RNAs (siRNAs) has not been achieved. Here we describe an siRNA architecture, divalent siRNA (di-siRNA), that supports potent, sustained gene silencing in the central nervous system (CNS) of mice and nonhuman primates following a single injection into the cerebrospinal fluid. Di-siRNAs are composed of two fully chemically modified, phosphorothioate-containing siRNAs connected by a linker. In mice, di-siRNAs induced the potent silencing of huntingtin, the causative gene in Huntington's disease, reducing messenger RNA and protein throughout the brain...
August 2019: Nature Biotechnology