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Small interfering RNA: Discovery, pharmacology and clinical development—An introductory review

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Ranasinghe, Priyanga, Addison, Melisande L., Dear, James W., Webb, David J.·2023·British Journal of Pharmacology
DOI 10.1111/bph.15972
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Abstract

Post‐transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference technology, using synthetic structurally well‐defined short double‐stranded RNA (small interfering RNA [siRNA]), has advanced rapidly in recent years. This introductory review describes the utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA‐induced silencing complex, siRNAs bind to specific complementary mRNAs, which are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off‐target effects. These have been overcome by chemical modification of siRNA and/or by utilising a range of delivery systems, increasing bioavailability and stability to allow successful clinical translation. Patisiran (hereditary transthyretin‐mediated amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial hypercholesterolaemia), which all use N ‐acetylgalactosamine (GalNAc) linkage for effective liver‐directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non‐communicable diseases (hypertension, cancer). Technological advances are paving the way for broader clinical use. Ongoing challenges remain in targeting organs beyond the liver and reaching special sites (e.g., brain). By overcoming these barriers, siRNA therapy has the potential to substantially widen its therapeutic impact.

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  • RNA interference therapeutics such as inclisiran generally exhibit lower immunogenicity than protein-based therapies, including monoclonal antibodies.

    “From a pharmacological standpoint, RNA interference therapeutics such as inclisiran generally exhibit lower immunogenicity than protein-based therapies, including monoclonal antibodies [62].”

    From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [62]

    The ‘Conjugation with ligands’ section (page not available) says most bioconjugates are inherently less immunogenic because of their low molecular size. It does not establish that RNA interference therapeutics generally, or inclisiran specifically, are less immunogenic than protein-based therapies or monoclonal antibodies. Section 4.1 compares siRNA therapies with antibodies on selectivity and manufacturing cost, not immunogenicity. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Ranasinghe, P., Addison, M. L., Dear, J. W., & Webb, D. J.
Affiliations
British Heart Foundation Centre for Cardiovascular Science (GB)
Corresponding author
Ranasinghe, Priyanga
ORCID
Venue
British Journal of Pharmacology
Publisher
Wiley
Published
2022-11-13
Volume
180
Issue
21
Pages
2697-2720
ISSN
  • 0007-1188 (ISSN-L)
  • 1476-5381
DOI
10.1111/bph.15972
OpenAlex
W4306399327
Cited by
138
References
13
Citations by year
2026: 39 · 2025: 36 · 2024: 40 · 2023: 22 · 2022: 1
FWCI
2.58
Type
journal article
Language
en
Open access
Licence
Locations
  • British Journal of Pharmacology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords
siRNA, RNA interference, post-transcriptional gene silencing, siRNA delivery systems, GalNAc-conjugated siRNA, patisiran, givosiran, lumasiran, inclisiran, off-target effects, siRNA therapeutics, brain targeting
MeSH terms
Humans, RNA, Double-Stranded, RNA, Messenger, Porphyrias, Hepatic, RNA Interference, RNA, Small Interfering

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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