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Cited by 677RNA Interference and Gene DeliveryCRISPR and Genetic EngineeringRNA Research and Splicing

Progress towards in Vivo Use of siRNAs

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Behlke, Mark A.·2006·Molecular Therapy
DOI 10.1016/j.ymthe.2006.01.001PMC PMC7106286
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Abstract

RNA interference (RNAi) has been extensively employed for in vivo research since its use was first demonstrated in mammalian cells 10 years ago. Design rules have improved, and it is now routinely possible to obtain reagents that suppress expression of any gene desired. At the same time, increased understanding of the molecular basis of unwanted side effects has led to the development of chemical modification strategies that mitigate these concerns. Delivery remains the single greatest hurdle to widespread adoption of in vivo RNAi methods. However, exciting advances have been made and new delivery systems under development may help to overcome these barriers. This review discusses advances in RNAi biochemistry and biology that impact in vivo use and provides an overview of select publications that demonstrate interesting applications of these principles. Emphasis is placed on work with synthetic, small interfering RNAs (siRNAs) published since the first installment of this review which appeared in 2006.

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  • Increasing the PS content of individual siRNA duplexes to 80% can limit RISC efficacy and increase toxicity.

    “However, increasing the PS content of individual siRNA duplexes to 80% can limit RNA-induced silencing complex (RISC) efficacy 17, 18 and increase toxicity19, 20.”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [17]

    The Chemical modification section says extensively PS-modified siRNA duplexes show reduced potency and/or toxicity. It does not specify 80% PS content or establish that the reduced potency results from impaired RISC efficacy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Increasing the percentage of PS modifications in the siRNA, either uniformly or strategically, may interfere with RISC and reduce tolerability.

    “Since increasing the percentage of PS modifications in the siRNA, either uniformly (i.e. every other nucleotide linkage) or strategically, may interfere with RISC 17, 18 and reduce tolerability, a multi-valency approach may be preferable for fine-tuning siRNA uptake and toxicity.”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [17]

    The Chemical modification section (page unavailable) says limited PS modification preserves siRNA potency, while extensive modification can reduce potency and/or cause toxicity. It does not say that PS modification interferes with RISC or assess an every-other-linkage pattern, so those specifics are unsupported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Behlke, M. A.
Affiliations
Integrated DNA Technologies (United States) (US)
Corresponding author
Behlke, Mark A.
ORCID
Behlke, Mark A.
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2006-04
Volume
13
Issue
4
Pages
644-670
ISSN
1525-0016 (ISSN-L)
DOI
10.1016/j.ymthe.2006.01.001
PMC
PMC7106286
OpenAlex
W2141547126
Cited by
677
References
8
Citations by year
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FWCI
4.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
RNA interference, siRNA, siRNA therapeutics, gene silencing, cancer therapy, antiviral therapy, functional genomics, target validation, siRNA delivery
MeSH terms
Animals, Immunity, Innate, Liposomes, Mammals, Oligonucleotides, Oligonucleotides, Antisense, Drug Delivery Systems, RNA Interference, RNA, Small Interfering

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