Journal
NATURE BIOTECHNOLOGY
Volume 37, Issue 8, Pages 884-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41587-019-0205-0
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Funding
- NIH/NINDS [R01 NS104022]
- NIH/OD [S10 OD020012]
- CHDI [A-6119]
- Alzheimer's Drug Discovery Foundation [20170101]
- Milton-Safenowitz Fellowship [17-PDF-363]
- Berman-Topper Fund
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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.
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