RNA Therapeutics Institute Publications

Title

A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system

Authors

Julia F. Alterman, University of Massachusetts Medical SchoolFollow
Bruno M. D. C. Godinho, University of Massachusetts Medical SchoolFollow
Matthew R. Hassler, University of Massachusetts Medical SchoolFollow
Chantal M. Ferguson, University of Massachusetts Medical SchoolFollow
Dimas Echeverria, University of Massachusetts Medical SchoolFollow
Ellen Sapp, Massachusetts General Institute for Neurodegenerative Disease, Boston
Reka A. Haraszti, University of Massachusetts Medical SchoolFollow
Andrew H. Coles, University of Massachusetts Medical SchoolFollow
Faith Conroy, University of Massachusetts Medical SchoolFollow
Rachael Miller, University of Massachusetts Medical SchoolFollow
Loic Roux, University of Massachusetts Medical SchoolFollow
Paul Yan, University of Massachusetts Medical SchoolFollow
Emily G. Knox, University of Massachusetts Medical SchoolFollow
Anton A. Turanov, University of Massachusetts Medical SchoolFollow
Robert M. King, University of Massachusetts Medical SchoolFollow
Gwladys Gernoux, University of Massachusetts Medical SchoolFollow
Christian Mueller, University of Massachusetts Medical SchoolFollow
Heather Gray-Edwards, University of Massachusetts Medical SchoolFollow
Richard P. Moser, University of Massachusetts Medical SchoolFollow
N Bishop, University of Massachusetts Medical SchoolFollow
Samer M. Jaber, University of Massachusetts Medical SchoolFollow
Matthew J. Gounis, University of Massachusetts Medical SchoolFollow
Miguel Sena-Esteves, University of Massachusetts Medical SchoolFollow
Athma A. Pai, University of Massachusetts Medical SchoolFollow
Marian DiFiglia, Massachusetts General Institute for Neurodegenerative Disease, Boston
Neil Aronin, University of Massachusetts Medical SchoolFollow
Anastasia Khvorova, University of Massachusetts Medical SchoolFollow

UMMS Affiliation

RNA Therapeutics Institute; Department of Medicine; Department of Radiology, New England Center for Stroke Research; Horae Gene Therapy Center; Department of Pediatrics; Department of Neurosurgery; Department of Animal Medicine; Department of Pathology; Department of Neurology; Program in Molecular Medicine; Graduate School of Biomedical Sciences, Interdisciplinary Graduate Program; Graduate School of Biomedical Sciences, Translational Science Program

Publication Date

2019-08-02

Document Type

Article

Disciplines

Biochemistry, Biophysics, and Structural Biology | Biotechnology | Genetics and Genomics | Nervous System Diseases | Neuroscience and Neurobiology | Therapeutics

Abstract

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.

DOI of Published Version

10.1038/s41587-019-0205-0

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

Journal/Book/Conference Title

Nature biotechnology

Related Resources

Link to Article in PubMed

PubMed ID

31375812

Share

COinS