Nature biotechnology · 2019
A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Alterman Julia F, Godinho Bruno M D C, Hassler Matthew R, Ferguson Chantal M, Echeverria Dimas, Sapp Ellen, Haraszti Reka A, Coles Andrew H, Conroy Faith, Miller Rachael, Roux Loic, Yan Paul, Knox Emily G, Turanov Anton A, King Robert M, Gernoux Gwladys, Mueller Christian, Gray-Edwards Heather L, Moser Richard P, Bishop Nina C, Jaber Samer M, Gounis Matthew J, Sena-Esteves Miguel, Pai Athma A, DiFiglia Marian, Aronin Neil, Khvorova Anastasia
Аннотация
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. Silencing persisted for at least 6 months, with the degree of gene silencing correlating to levels of guide strand tissue accumulation. In cynomolgus macaques, a bolus injection of di-siRNA showed substantial distribution and robust silencing throughout the brain and spinal cord without detectable toxicity and with minimal off-target effects. This siRNA design may enable RNA interference-based gene silencing in the CNS for the treatment of neurological disorders.