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Amplifying gene expression with RNA-targeted therapeutics

Nature Reviews Drug Discovery volume 22, pages 539–561 (2023)Cite this article

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Abstract

Many diseases are caused by insufficient expression of mutated genes and would benefit from increased expression of the corresponding protein. However, in drug development, it has been historically easier to develop drugs with inhibitory or antagonistic effects. Protein replacement and gene therapy can achieve the goal of increased protein expression but have limitations. Recent discoveries of the extensive regulatory networks formed by non-coding RNAs offer alternative targets and strategies to amplify the production of a specific protein. In addition to RNA-targeting small molecules, new nucleic acid-based therapeutic modalities that allow highly specific modulation of RNA-based regulatory networks are being developed. Such approaches can directly target the stability of mRNAs or modulate non-coding RNA-mediated regulation of transcription and translation. This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic.

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Fig. 1: Overview of strategies to increase protein production.
Fig. 2: Biology of protein upregulation.
Fig. 3: NBTs that increase mRNA abundance.
Fig. 4: NBTs and small molecules targeting mRNA translation.

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Acknowledgements

This work was supported in part by NIH grants AA29924 and AG079373 and the State of Florida grant 23A17. The authors thank Michael Brown for helpful advice, comments and ideas and for critically reading the manuscript.

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Authors and Affiliations

  1. OPKO Health, Miami, FL, USA

    Olga Khorkova

  2. Center for Therapeutic Innovation, University of Miami, Miami, FL, USA

    Olga Khorkova, Jack Stahl, Aswathy Joji, Claude-Henry Volmar & Claes Wahlestedt

  3. Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA

    Jack Stahl, Claude-Henry Volmar & Claes Wahlestedt

  4. Department of Chemistry, University of Miami, Miami, FL, USA

    Aswathy Joji & Claes Wahlestedt

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The authors contributed equally to all aspects of the article.

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Correspondence to Claes Wahlestedt.

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Competing interests

C.W. is a co-founder of Epigenetix and Jupiter Neurosciences, Inc., and serves on scientific advisory boards of Camp4 Therapeutics, Cascade Biotechnology, Galatea Bio and Ribocure. O.K. is employed by OPKO Health.

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Supplementary information

Glossary

Benner base Z

A synthetic nucleotide analogue that can form a non-hydrogen-bonded base pair with another non-natural base F; the shapes of the Z and F bases are similar to A and T, respectively.

Enhancer–promoter looping

Repositioning of enhancers in physical proximity of promoters necessary for activation of gene expression, made possible by the formation of a chromosomal DNA loop.

Enhancer RNAs

(eRNAs). Long and short non-coding RNAs transcribed from enhancer regions.

Integrator complex

Multi-protein complex containing IntS11 RNA endonuclease, which cleaves nascent RNAs transcribed by RNA polymerase II; cleavage generates small nuclear RNAs and enhancer RNAs.

Internal ribosome entry sites

(IRESs). Three-dimensional RNA structures that facilitate cap-independent transcription.

Long non-coding RNA

(lncRNA). RNA transcripts that are >200 nucleotides and do not have long open reading frames.

MicroRNAs

(miRNAs). Short (20–30 nucleotides) double-stranded regulatory non-coding RNAs that can be generated endogenously; can also refer to synthetic miRNA mimics.

Natural antisense transcripts

(NATs). Long non-coding RNAs expressed from the chromosome strand opposite to the protein-coding gene.

Nucleic acid-based therapeutics

(NBTs). Therapeutic agents derived from nucleic acids, including antisense oligonucleotides, small interfering RNAs, therapeutic mRNAs and vectorized constructs expressing any combination of the above.

Pause-controlled genes

Genes of which the expression is regulated by RNA polymerase II pausing.

Polyadenylation

Addition of a polyA tail to the 5′ end of an RNA.

Promoter RNAs

(pRNAs). Long and short non-coding RNA (ncRNA) transcribed from promoter regions.

Proteolysis-targeting chimaeras

(PROTACs). Small molecules that tag proteins for proteasomal degradation.

Toxic exons

Naturally occurring exons that contain a premature stop codon or otherwise interfere with protein translation from the transcripts that incorporate them.

Upstream open reading frames

(uORFs). Short open reading frames present in 5′ untranslated regions of some mRNAs.

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Khorkova, O., Stahl, J., Joji, A. et al. Amplifying gene expression with RNA-targeted therapeutics. Nat Rev Drug Discov 22, 539–561 (2023). https://doi.org/10.1038/s41573-023-00704-7

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