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Cited by 497RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryVirus-based gene therapy research

The growth of siRNA-based therapeutics: updated clinical studies

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Zhang, M. May, Bahal, Raman, Rasmussen, Theodore P., Manautou, José E., Zhong, Xiao-bo·2021·Biochemical Pharmacology
DOI 10.1016/j.bcp.2021.114432PMC PMC8187268
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Abstract

More than two decades after the natural gene-silencing mechanism of RNA interference was elucidated, small interfering RNA (siRNA)-based therapeutics have finally broken into the pharmaceutical market. With three agents already approved and many others in advanced stages of the drug development pipeline, siRNA drugs are on their way to becoming a standard modality of pharmacotherapy. The majority of late-stage candidates are indicated for rare or orphan diseases, whose patients have an urgent need for novel and effective therapies. Additionally, there are agents that have the potential to meet the need of a broader population. Inclisiran, for instance, is being developed for hypercholesterolemia and has shown benefit in patients who are uncontrolled even after maximal statin therapy. This review provides a brief overview of mechanisms of siRNA action, physiological barriers to its delivery and activity, and the most common chemical modifications and delivery platforms used to overcome these barriers. Furthermore, this review presents comprehensive profiles of the three approved siRNA drugs (patisiran, givosiran, and lumasiran) and the seven other siRNA candidates in Phase 3 clinical trials (vutrisiran, nedosiran, inclisiran, fitusiran, teprasiran, cosdosiran, and tivanisiran), summarizing their modifications and delivery strategies, disease-specific mechanisms of action, updated clinical trial status, and future outlooks.

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  • The FDA has approved four siRNA-based therapeutics including inclisiran which targets PCSK9 for hypercholesterolaemia.

    “The FDA has approved four siRNA-based therapeutics including the recently approved drug inclisiran which targets PCSK9 for the treatment of hypercholesterolaemia”

    From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Zhang et al 2021

    The Abstract identifies three approved siRNA drugs and lists inclisiran among Phase 3 candidates, not approved drugs. The Inclisiran section says FDA approval was expected in the future. The paper does support that inclisiran targets PCSK9 for hypercholesterolemia, but contradicts the claimed FDA approval and count of four. (LLM, conf=0.94)

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Cited by

Sorted by citations

Authors
Zhang, M. M., Bahal, R., Rasmussen, T. P., Manautou, J. E., & Zhong, X.-B.
Affiliations
University of Connecticut (US)
Corresponding author
Zhong, Xiao-bo
ORCID
Venue
Biochemical Pharmacology
Publisher
Elsevier BV
Published
2021-07
Volume
189
Pages
114432
ISSN
0006-2952 (ISSN-L)
DOI
10.1016/j.bcp.2021.114432
PMC
PMC8187268
OpenAlex
W3121560287
Cited by
497
References
10
Citations by year
2026: 48 · 2025: 96 · 2024: 119 · 2023: 106 · 2022: 95 · 2021: 33
FWCI
9.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochemical Pharmacology (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of General Medical Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
siRNA therapeutics, RNA interference, siRNA delivery, siRNA chemical modification, patisiran, givosiran, lumasiran, inclisiran, vutrisiran, fitusiran, hypercholesterolemia
MeSH terms
Drug Development, Animals, Clinical Trials as Topic, Humans, Hypercholesterolemia, Nervous System Diseases, Genetic Therapy, Gene Transfer Techniques, RNA, Small Interfering

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