A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system
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
Biochemistry, Biophysics, and Structural Biology | Biotechnology | Genetics and Genomics | Nervous System Diseases | Neuroscience and Neurobiology | Therapeutics
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.
small interfering RNAs, siRNAs, gene silencing, central nervous system
DOI of Published Version
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
Alterman JF, Godinho B, Hassler MR, Ferguson CM, Echeverria D, Sapp E, Haraszti RA, Coles AH, Conroy F, Miller R, Roux L, Yan P, Knox EG, Turanov AA, King RM, Gernoux G, Mueller C, Gray-Edwards H, Moser RP, Bishop N, Jaber SM, Gounis MJ, Sena-Esteves M, Pai AA, DiFiglia M, Aronin N, Khvorova A. (2019). A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system. RNA Therapeutics Institute Publications. https://doi.org/10.1038/s41587-019-0205-0. Retrieved from https://escholarship.umassmed.edu/rti_pubs/56