A combinatorial approach for achieving CNS-selective RNAi Article Swipe
Chantal Ferguson
,
Bruno M.D.C. Godinho
,
Dimas Echeverria
,
Matthew Hassler
,
Lorenc Vangjeli
,
Jacquelyn Sousa
,
Nicholas McHugh
,
Julia F. Alterman
,
Vignesh Hariharan
,
Pranathi M. Krishnamurthy
,
Jonathan K. Watts
,
Eveny Rogaev
,
Anastasia Khvorova
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1093/nar/gkae100
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1093/nar/gkae100
RNA interference (RNAi) is an endogenous process that can be harnessed using chemically modified small interfering RNAs (siRNAs) to potently modulate gene expression in many tissues. The route of administration and chemical architecture are the primary drivers of oligonucleotide tissue distribution, including siRNAs. Independently of the nature and type, oligonucleotides are eliminated from the body through clearance tissues, where their unintended accumulation may result in undesired gene modulation. Divalent siRNAs (di-siRNAs) administered into the CSF induce robust gene silencing throughout the central nervous system (CNS). Upon clearance from the CSF, they are mainly filtered by the kidneys and liver, with the most functionally significant accumulation occurring in the liver. siRNA- and miRNA-induced silencing can be blocked through substrate inhibition using single-stranded, stabilized oligonucleotides called antagomirs or anti-siRNAs. Using APOE as a model target, we show that undesired di-siRNA-induced silencing in the liver can be mitigated through administration of liver targeting GalNAc-conjugated anti-siRNAs, without impacting CNS activity. Blocking unwanted hepatic APOE silencing achieves fully CNS-selective silencing, essential for potential clinical translation. While we focus on CNS/liver selectivity, coadministration of differentially targeting siRNA and anti-siRNAs can be adapted as a strategy to achieve tissue selectivity in different organ combinations.
Related Topics
Concepts
Small interfering RNA
Gene silencing
RNA interference
Biology
Trans-acting siRNA
Oligonucleotide
Cell biology
RNA silencing
microRNA
Molecular biology
RNA
Gene
Biochemistry
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1093/nar/gkae100
- https://academic.oup.com/nar/advance-article-pdf/doi/10.1093/nar/gkae100/56668662/gkae100.pdf
- OA Status
- gold
- Cited By
- 6
- References
- 39
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4391766762
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4391766762Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1093/nar/gkae100Digital Object Identifier
- Title
-
A combinatorial approach for achieving CNS-selective RNAiWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-02-13Full publication date if available
- Authors
-
Chantal Ferguson, Bruno M.D.C. Godinho, Dimas Echeverria, Matthew Hassler, Lorenc Vangjeli, Jacquelyn Sousa, Nicholas McHugh, Julia F. Alterman, Vignesh Hariharan, Pranathi M. Krishnamurthy, Jonathan K. Watts, Eveny Rogaev, Anastasia KhvorovaList of authors in order
- Landing page
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https://doi.org/10.1093/nar/gkae100Publisher landing page
- PDF URL
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https://academic.oup.com/nar/advance-article-pdf/doi/10.1093/nar/gkae100/56668662/gkae100.pdfDirect link to full text PDF
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
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https://academic.oup.com/nar/advance-article-pdf/doi/10.1093/nar/gkae100/56668662/gkae100.pdfDirect OA link when available
- Concepts
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Small interfering RNA, Gene silencing, RNA interference, Biology, Trans-acting siRNA, Oligonucleotide, Cell biology, RNA silencing, microRNA, Molecular biology, RNA, Gene, BiochemistryTop concepts (fields/topics) attached by OpenAlex
- Cited by
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6Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 5, 2024: 1Per-year citation counts (last 5 years)
- References (count)
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39Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| primary_location.source.issn | 0305-1048, 1362-4954, 1362-4962 |
| primary_location.source.type | journal |
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| primary_location.source.issn_l | 0305-1048 |
| primary_location.source.is_core | True |
| primary_location.source.is_in_doaj | True |
| primary_location.source.display_name | Nucleic Acids Research |
| primary_location.source.host_organization | https://openalex.org/P4310311648 |
| primary_location.source.host_organization_name | Oxford University Press |
| primary_location.source.host_organization_lineage | https://openalex.org/P4310311648, https://openalex.org/P4310311647 |
| primary_location.source.host_organization_lineage_names | Oxford University Press, University of Oxford |
| primary_location.license | other-oa |
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| primary_location.version | publishedVersion |
| primary_location.raw_type | journal-article |
| primary_location.license_id | https://openalex.org/licenses/other-oa |
| primary_location.is_accepted | True |
| primary_location.is_published | True |
| primary_location.raw_source_name | Nucleic Acids Research |
| primary_location.landing_page_url | https://doi.org/10.1093/nar/gkae100 |
| publication_date | 2024-02-13 |
| publication_year | 2024 |
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| abstract_inverted_index.of | 29, 38, 45, 148, 178 |
| abstract_inverted_index.on | 174 |
| abstract_inverted_index.or | 126 |
| abstract_inverted_index.to | 19, 190 |
| abstract_inverted_index.we | 134, 172 |
| abstract_inverted_index.CNS | 155 |
| abstract_inverted_index.CSF | 75 |
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| abstract_inverted_index.and | 31, 48, 98, 111, 182 |
| abstract_inverted_index.are | 34, 51, 92 |
| abstract_inverted_index.can | 9, 114, 143, 184 |
| abstract_inverted_index.for | 167 |
| abstract_inverted_index.may | 63 |
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| abstract_inverted_index.CSF, | 90 |
| abstract_inverted_index.RNAs | 17 |
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| abstract_inverted_index.from | 53, 88 |
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| abstract_inverted_index.fully | 163 |
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| abstract_inverted_index.model | 132 |
| abstract_inverted_index.organ | 196 |
| abstract_inverted_index.route | 28 |
| abstract_inverted_index.siRNA | 181 |
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| abstract_inverted_index.their | 60 |
| abstract_inverted_index.type, | 49 |
| abstract_inverted_index.using | 12, 120 |
| abstract_inverted_index.where | 59 |
| abstract_inverted_index.(CNS). | 85 |
| abstract_inverted_index.(RNAi) | 3 |
| abstract_inverted_index.called | 124 |
| abstract_inverted_index.induce | 76 |
| abstract_inverted_index.liver, | 99 |
| abstract_inverted_index.liver. | 109 |
| abstract_inverted_index.mainly | 93 |
| abstract_inverted_index.nature | 47 |
| abstract_inverted_index.result | 64 |
| abstract_inverted_index.robust | 77 |
| abstract_inverted_index.siRNA- | 110 |
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| abstract_inverted_index.achieve | 191 |
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| abstract_inverted_index.modified | 14 |
| abstract_inverted_index.modulate | 21 |
| abstract_inverted_index.potently | 20 |
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| abstract_inverted_index.tissues. | 26 |
| abstract_inverted_index.unwanted | 158 |
| abstract_inverted_index.CNS/liver | 175 |
| abstract_inverted_index.activity. | 156 |
| abstract_inverted_index.clearance | 57, 87 |
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| abstract_inverted_index.essential | 166 |
| abstract_inverted_index.harnessed | 11 |
| abstract_inverted_index.impacting | 154 |
| abstract_inverted_index.including | 42 |
| abstract_inverted_index.mitigated | 145 |
| abstract_inverted_index.occurring | 106 |
| abstract_inverted_index.potential | 168 |
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| abstract_inverted_index.substrate | 118 |
| abstract_inverted_index.targeting | 150, 180 |
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| abstract_inverted_index.antagomirs | 125 |
| abstract_inverted_index.chemically | 13 |
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| abstract_inverted_index.inhibition | 119 |
| abstract_inverted_index.silencing, | 165 |
| abstract_inverted_index.stabilized | 122 |
| abstract_inverted_index.throughout | 80 |
| abstract_inverted_index.unintended | 61 |
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| abstract_inverted_index.interfering | 16 |
| abstract_inverted_index.modulation. | 68 |
| abstract_inverted_index.selectivity | 193 |
| abstract_inverted_index.significant | 104 |
| abstract_inverted_index.accumulation | 62, 105 |
| abstract_inverted_index.administered | 72 |
| abstract_inverted_index.anti-siRNAs, | 152 |
| abstract_inverted_index.anti-siRNAs. | 127 |
| abstract_inverted_index.architecture | 33 |
| abstract_inverted_index.functionally | 103 |
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| abstract_inverted_index.selectivity, | 176 |
| abstract_inverted_index.translation. | 170 |
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| abstract_inverted_index.Independently | 44 |
| abstract_inverted_index.combinations. | 197 |
| abstract_inverted_index.distribution, | 41 |
| abstract_inverted_index.miRNA-induced | 112 |
| abstract_inverted_index.administration | 30, 147 |
| abstract_inverted_index.differentially | 179 |
| abstract_inverted_index.oligonucleotide | 39 |
| abstract_inverted_index.coadministration | 177 |
| abstract_inverted_index.di-siRNA-induced | 138 |
| abstract_inverted_index.oligonucleotides | 50, 123 |
| abstract_inverted_index.single-stranded, | 121 |
| abstract_inverted_index.GalNAc-conjugated | 151 |
| cited_by_percentile_year.max | 98 |
| cited_by_percentile_year.min | 90 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 13 |
| citation_normalized_percentile.value | 0.84784804 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |