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Target mRNA inhibition by oligonucleotide drugs in man

Helen L Lightfoot1, Jonathan Hall

  • 1Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, CH-8093 Zürich, Switzerland.

Nucleic Acids Research
|September 20, 2012
PubMed

Insights

Oligonucleotide drugs show successful delivery and target engagement in clinical trials. However, novel targets outside the drugable genome present challenges, highlighting the equal importance of target selection and validation for drug development success.

Area of Science:

  • Pharmacology
  • Genetics
  • Drug Development

Background:

  • Oligonucleotide delivery in vivo is a major challenge for oligonucleotide drug development.
  • Many oligonucleotide drugs in late-stage clinical trials demonstrate target engagement in relevant human tissues.

Purpose of the Study:

  • To analyze the delivery efficiency and target validation of oligonucleotide drugs in clinical trials.
  • To assess the role of target selection and validation in the success of oligonucleotide therapeutics.

Main Methods:

  • Analysis of 26 oligonucleotide drugs in late-stage clinical trials.
  • Evaluation of mRNA and/or protein level suppression in target cells.
  • Assessment of drug targets relative to the 'drugable genome'.

Main Results:

  • At least half of analyzed drugs showed target suppression in human tissues (liver, muscle, bone marrow, lung, blood, solid tumors).
  • The majority of oligonucleotide drug targets are outside the conventional drugable genome.
  • A subset of novel targets has been validated by these drugs, despite high-risk mechanisms.

Conclusions:

  • Oligonucleotide drug delivery to target tissues appears effective in many cases.
  • Target selection and validation are critical factors for the success of oligonucleotide therapeutics, on par with delivery challenges.

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