Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep
Open accessAbstract
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.
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Divalent siRNA was not effective throughout the striatum of Dorset sheep.
“Notably, C16-siRNA did not achieve knockdown in the striatum of rats, and the divalent siRNA was not effective throughout the striatum of Dorset sheep.22,49”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [49]
The Results section on HTT mRNA silencing reports incomplete striatal efficacy for some routes: intrathecal-catheter delivery had no detectable activity in the putamen, and intrastriatal injection produced no silencing on the contralateral side. But it also reports substantial silencing in the caudate and putamen with other routes, so the unqualified claim that divalent siRNA was not effective throughout the striatum overstates the finding. No page number is available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCSF access points for oligonucleotide injections can change biodistribution.
“We also showed that CSF access points for oligonucleotide injections can change biodistribution [46].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [46]
C16-siRNA did not achieve knockdown in the striatum of rats.
“Notably, C16-siRNA did not achieve knockdown in the striatum of rats, and the divalent siRNA was not effective throughout the striatum of Dorset sheep.22,49”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [49]
The Results section reports di-siRNA silencing in Dorset sheep, including variable effects in the caudate and putamen. Our copy does not report whether C16-siRNA achieved striatal knockdown in rats; searches for C16-siRNA and rat striatal knockdown found no passage addressing that claim. (LLM, conf=0.76)
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- Authors
- Ferguson, C. M., Godinho, B. M. D. C., Alterman, J. F., Coles, A. H., Hassler, M., Echeverria, D., Gilbert, J. W., Knox, E. G., Caiazzi, J., Haraszti, R. A., King, R. M., Taghian, T., Puri, A., Moser, R. P., Gounis, M. J., Aronin, N., Gray-Edwards, H., & Khvorova, A.
- Affiliations
- RNA Therapeutics Institute and
- Worcester Polytechnic Institute (US)
- University of Massachusetts Chan Medical School (US)
- Neurointerventional Radiology,
- Department of Neurosurgery, and
- Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
- Corresponding author
- Khvorova, Anastasia
- ORCID
- Venue
- JCI Insight
- Published
- 2021-12-22
- Volume
- 6
- Issue
- 24
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC8783676
- OpenAlex
- W4200588978
- Cited by
- 27
- References
- 36
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 8 · 2023: 6 · 2022: 1
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JCI Insight (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- CHDI Foundation (CHDI)
- NIH Clinical Center (5R01 NS10433-03,)
- National Research Service Award (1F30AG066373)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- siRNA therapeutics, intrathecal catheter, intracerebroventricular administration, intrastriatal injection, Dorset sheep, dosing regimen, repeated dosing, gene silencing
- MeSH terms
- Animals, Drug Administration Routes, Sheep, Genetic Therapy, RNA, Small Interfering
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