Modulation of RNA Splicing by Oligonucleotides: Mechanisms of Action and Therapeutic Implications

Olga V. Sergeeva, Evgeniya Y. Shcherbinina, Noam Shomron, Timofei S. Zatsepin

Research output: Contribution to journalReview articlepeer-review

Abstract

Dysregulation of RNA splicing causes many diseases and disorders. Several therapeutic approaches have been developed to correct aberrant alternative splicing events for the treatment of cancers and hereditary diseases, including gene therapy and redirecting splicing, using small molecules or splice switching oligonucleotides (SSO). Significant advances in the chemistry and pharmacology of nucleic acid have led to the development of clinically approved SSO drugs for the treatment of spinal muscular dystrophy and Duchenne muscular dystrophy (DMD). In this review, we discuss the mechanisms of SSO action with emphasis on "less common" approaches to modulate alternative splicing, including bipartite and bifunctional SSO, oligonucleotide decoys for splice factors and SSO-mediated mRNA degradation via AS-NMD and NGD pathways. We briefly discuss the current progress and future perspectives of SSO therapy for rare and ultrarare diseases.

Original languageEnglish
Pages (from-to)123-138
Number of pages16
JournalNucleic Acid Therapeutics
Volume32
Issue number3
DOIs
StatePublished - 1 Jun 2022

Keywords

  • molecular mechanism
  • oligonucleotide therapeutics
  • splice switching

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