A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system
Authors
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
Moser, Richard P.
Bishop, N
Jaber, Samer M.
Gounis, Matthew J.
Sena-Esteves, Miguel
Pai, Athma A.
DiFiglia, Marian
Aronin, Neil
Khvorova, Anastasia
UMass Chan Affiliations
Graduate School of Biomedical Sciences, Translational Science ProgramGraduate School of Biomedical Sciences, Interdisciplinary Graduate Program
Program in Molecular Medicine
Department of Neurology
Department of Pathology
Department of Animal Medicine
Department of Neurosurgery
Department of Pediatrics
Horae Gene Therapy Center
Department of Radiology, New England Center for Stroke Research
Department of Medicine
RNA Therapeutics Institute
Document Type
Journal ArticlePublication Date
2019-08-02Keywords
small interfering RNAssiRNAs
gene silencing
central nervous system
Biochemistry, Biophysics, and Structural Biology
Biotechnology
Genetics and Genomics
Nervous System Diseases
Neuroscience and Neurobiology
Therapeutics
Metadata
Show full item recordAbstract
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.Source
Nat Biotechnol. 2019 Aug;37(8):884-894. doi: 10.1038/s41587-019-0205-0. Epub 2019 Aug 2. Link to article on publisher's site
DOI
10.1038/s41587-019-0205-0Permanent Link to this Item
http://hdl.handle.net/20.500.14038/48848PubMed ID
31375812Notes
This paper was selected in March 2021 for Nature Biotechnology's 25th Anniversary collection of the journal's top 25 landmark papers.
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10.1038/s41587-019-0205-0