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Cited by 1,551RNA Interference and Gene DeliveryCancer-related molecular mechanisms researchMicroRNA in disease regulation

Noncoding RNA therapeutics—Challenges and potential solutions

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Winkle, Melanie, El-Daly, Sherien M., Fabbri, Muller, Calin, George A.·2021·Nature Reviews Drug Discovery
DOI 10.1038/s41573-021-00219-zPMC PMC8212082
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Abstract

Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach for the treatment of cancers, as well as many other diseases. Over the past decade, substantial effort has been made towards the clinical application of RNA-based therapeutics, employing mostly antisense oligonucleotides and small interfering RNAs, with several gaining FDA approval. However, trial results have so far been ambivalent, with some studies reporting potent effects whereas others demonstrated limited efficacy or toxicity. Alternative entities such as antimiRNAs are undergoing clinical testing, and lncRNA-based therapeutics are gaining interest. In this Perspective, we discuss key challenges facing ncRNA therapeutics - including issues associated with specificity, delivery and tolerability - and focus on promising emerging approaches that aim to boost their success.

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  • It is estimated that 30% of human genes are regulated by miRNAs.

    “Very interestingly, it is estimated that 30% of human genes are regulated by miRNAs [53,61].”

    From Revisiting Epigenetics Fundamentals and Its Biomedical Implications (2024) · cites this paper as [61]

    The Introduction (page unavailable) describes miRNAs as gene regulators. The hurdle of specificity (page unavailable) reports that one miRNA cluster can affect about 14% of the transcriptome in leukaemic cells, but it does not support the estimate that miRNAs regulate 30% of human genes. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • lncRNAs can be bidirectional and can come from intronic or intergenic sequences, or from disruption of open reading frames or chromosomal rearrangements.

    “These lncRNAs can be bidirectional, and they can come from intronic or intergenic sequences. They can also be derived from the disruption of open reading frames or chromosomal rearrangements.”

    From Revisiting Epigenetics Fundamentals and Its Biomedical Implications (2024) · cites this paper as [61]

    The Introduction (page unavailable) describes lncRNAs transcribed antisense to coding genes, and the References list a study of large intergenic noncoding RNAs. These passages support some variation in lncRNA location or transcription direction, but they do not establish the claimed bidirectionality or derivation from intronic sequences, disrupted open reading frames, or chromosomal rearrangements. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • miRNAs are derived from transcripts, intronic and intergenic sequences, form a unique hairpin structure processed into mature form, and mediate gene silencing at the post-transcriptional level by coupling to an RNA-induced silencing complex in the cytoplasm.

    “This type of ncRNA is derived from transcripts, intronic and intergenic sequences, that form a unique hairpin structure to be processed into their mature form, which allows them to mediate gene silencing at the post-transcriptional level by coupling to an RNA-induced silencing complex in the cytoplasm.”

    From Revisiting Epigenetics Fundamentals and Its Biomedical Implications (2024) · cites this paper as [61]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Mature miRNAs are RNA molecules around 20 nucleotides in length, widely conserved among species, with diverse functions, and involved in regulation of gene expression in multicellular eukaryotes and some unicellular eukaryotes.

    “Mature miRNAs are RNA molecules of around 20 nucleotides in length that are widely conserved among species with diverse functions and involved in the regulation of gene expression in multicellular eukaryotes and some unicellular eukaryotes.”

    From Revisiting Epigenetics Fundamentals and Its Biomedical Implications (2024) · cites this paper as [61]

    The Introduction describes miRNAs as highly conserved, 17–25-nucleotide RNAs that regulate genes, and the specificity section describes their ability to target multiple mRNAs. The cited passages do not establish that this regulation occurs in some unicellular eukaryotes; the claim's organismal scope is therefore not fully supported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • lncRNAs serve as scaffolds for multiple proteins necessary for the assembly of ribonucleoprotein complexes, which can modulate the marks on histone tails.

    “It is currently recognized that lncRNAs can serve as precursors of siRNAs; they can serve to modulate gene expression through the recruitment of chromatin-modifying enzymes, and they also serve as scaffolds for multiple proteins necessary for the assembly of ribonucleoprotein complexes, which can modulate the marks on histone tails [53,61].”

    From Revisiting Epigenetics Fundamentals and Its Biomedical Implications (2024) · cites this paper as [61]

    The Introduction (page unavailable) says lncRNAs interact with proteins and can influence epigenetic marks, supporting the claim’s broad mechanism. It does not describe lncRNAs scaffolding multiple proteins to assemble ribonucleoprotein complexes or specify modifications to histone tails. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Winkle, M., El-Daly, S. M., Fabbri, M., & Calin, G. A.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • University of Hawaii Cancer Center (US)
ORCID
Venue
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Published
2021-06-18
Volume
20
Issue
8
Pages
629-651
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
DOI
10.1038/s41573-021-00219-z
PMC
PMC8212082
OpenAlex
W3171835979
Cited by
1,551
References
14
Citations by year
2026: 158 · 2025: 293 · 2024: 393 · 2023: 357 · 2022: 286 · 2021: 62 · 2014: 1
FWCI
29.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Drug Discovery (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Defense (CA160445P1)
  • CLL Global Research Foundation
  • Science and Technology Development Fund
  • National Institutes of Health (CA160445P1, UH3TR000943, UH3TR00943‐01)
  • National Cancer Institute (R01CA219024, CA160445P1, R01CA182905, R01CA222007, R01CA215753, P30CA071789)
  • National Institute of General Medical Sciences (R01GM122775)
  • National Center for Advancing Translational Sciences (UH3TR00943‐01)
  • Moonshot Research and Development Program
  • Common Fund
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Keywords
microRNA, long non-coding RNA, antisense oligonucleotides, siRNA, RNA delivery, tolerability, clinical translation
MeSH terms
Animals, Humans, Neoplasms, Genetic Therapy, Molecular Targeted Therapy, RNA, Long Noncoding

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