UMMS Affiliation

RNA Therapeutics Institute; Department of Radiology, New England Center for Stroke Research; Neurointerventional Radiology; Department of Neurosurgery; Program in Molecular Medicine; Graduate School of Biomedical Sciences

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Genetics and Genomics | Neuroscience and Neurobiology | Nucleic Acids, Nucleotides, and Nucleosides | Therapeutics


siRNAs comprise a class of drugs that can be programmed to silence any target gene. Chemical engineering efforts resulted in development of divalent siRNAs (di-siRNAs), which support robust and long-term efficacy in rodent and nonhuman primate brains upon direct cerebrospinal fluid (CSF) administration. Oligonucleotide distribution in the CNS is nonuniform, limiting clinical applications. The contribution of CSF infusion placement and dosing regimen on relative accumulation, specifically in the context of large animals, is not well characterized. To our knowledge, we report the first systemic, comparative study investigating the effects of 3 routes of administration - intrastriatal (i.s.), i.c.v., and intrathecal catheter to the cisterna magna (ITC) - and 2 dosing regimens - single and repetitive via an implanted reservoir device - on di-siRNA distribution and accumulation in the CNS of Dorset sheep. CSF injections (i.c.v. and ITC) resulted in similar distribution and accumulation across brain regions. Repeated dosing increased homogeneity, with greater relative deep brain accumulation. Conversely, i.s. administration supported region-specific delivery. These results suggest that dosing regimen, not CSF infusion placement, may equalize siRNA accumulation and efficacy throughout the brain. These findings inform the planning and execution of preclinical and clinical studies using siRNA therapeutics in the CNS.


Gene therapy, Neurodegeneration, Neuroscience, RNA processing

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Copyright: © 2021, Ferguson et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

DOI of Published Version



Ferguson CM, Godinho BM, Alterman JF, Coles AH, Hassler M, Echeverria D, Gilbert JW, Knox EG, Caiazzi J, Haraszti RA, King RM, Taghian T, Puri A, Moser RP, Gounis MJ, Aronin N, Gray-Edwards H, Khvorova A. Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep. JCI Insight. 2021 Dec 22;6(24):e152203. doi: 10.1172/jci.insight.152203. PMID: 34935646. Link to article on publisher's site

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JCI insight

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Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.