Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep
Authors
Ferguson, Chantal M.Godinho, Bruno M D C
Alterman, Julia F.
Coles, Andrew H.
Hassler, Matthew R.
Echeverria, Dimas
Gilbert, James

Knox, Emily G.
Caiazzi, Jillian
Haraszti, Reka A
King, Robert M.
Taghian, Toloo
Puri, Ajit S.
Moser, Richard P.
Gounis, Matthew J.
Aronin, Neil
Gray-Edwards, Heather L
Khvorova, Anastasia
UMass Chan Affiliations
Graduate School of Biomedical SciencesProgram in Molecular Medicine
Department of Neurosurgery
Neurointerventional Radiology
Department of Radiology, New England Center for Stroke Research
RNA Therapeutics Institute
Document Type
Journal ArticlePublication Date
2021-12-22Keywords
Gene therapyNeurodegeneration
Neuroscience
RNA processing
Genetics and Genomics
Neuroscience and Neurobiology
Nucleic Acids, Nucleotides, and Nucleosides
Therapeutics
Metadata
Show full item recordAbstract
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.Source
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
DOI
10.1172/jci.insight.152203Permanent Link to this Item
http://hdl.handle.net/20.500.14038/48575PubMed ID
34935646Related Resources
Rights
Copyright: © 2021, Ferguson et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1172/jci.insight.152203
Scopus Count
Except where otherwise noted, this item's license is described as Copyright: © 2021, Ferguson et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.