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siRNA - Small Interfering RNAs02:30

siRNA - Small Interfering RNAs

Small interfering RNAs, or siRNAs, are short regulatory RNA molecules that can silence genes post-transcriptionally, as well as the transcriptional level in some cases. siRNAs are important for protecting cells against viral infections and silencing transposable genetic elements.
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the ATP-dependent...

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siRNA-optimized Modifications for Enhanced In Vivo Activity.

Denise M Kenski1, Gabor Butora, Aarron T Willingham

  • 1Sirna Therapeutics, a wholly owned subsidiary of Merck and Co., San Francisco, California, USA.

Molecular Therapy. Nucleic Acids
|January 25, 2013
PubMed
Summary

Novel 2'-O modifications enhance small interfering RNA (siRNA) potency and duration in vivo. These siRNA-optimized modifications, unlike older ones, improve therapeutic effectiveness when delivered via lipid nanoparticles.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Current small interfering RNA (siRNA) modifications like 2'-methoxy and 2'-fluoro improve stability and specificity but not potency.
  • These modifications were originally developed for antisense applications, not optimized for siRNA function.

Purpose of the Study:

  • To investigate novel siRNA-optimized 2'-O modifications, specifically 2'-O-benzyl and 2'-O-methyl-4-pyridine (2'-O-CH2Py(4)).
  • To determine the tolerability and impact of these modifications at various positions on the siRNA guide strand in vivo.
  • To assess if combining these modifications enhances siRNA potency and duration.

Main Methods:

  • Synthesized and tested siRNAs with 2'-O-benzyl and 2'-O-CH2Py(4) modifications at individual positions on the guide strand across five sequences.
  • Combined tolerated modifications at optimal positions to evaluate synergistic effects on siRNA activity.
  • Delivered modified siRNAs using lipid nanoparticles in vivo to assess potency and duration.

Main Results:

  • Both 2'-O-benzyl and 2'-O-CH2Py(4) modifications were tolerated at multiple positions on the siRNA guide strand in vivo.
  • Incorporation of 2'-O-benzyl was tolerated at four positions, while 2'-O-CH2Py(4) was tolerated at six positions.
  • Combining modifications, particularly at positions 8 and 15, significantly increased in vivo potency and duration compared to unmodified siRNAs.

Conclusions:

  • Novel siRNA-optimized 2'-O modifications, 2'-O-benzyl and 2'-O-CH2Py(4), enhance in vivo potency and duration.
  • Optimal placement of these modifications on the guide strand is crucial for maximizing siRNA therapeutic potential.
  • These findings are vital for the advancement of RNA-based therapeutics.