RNA Activation-A Novel Approach to Therapeutically Upregulate Gene Transcription.

Choon Ping Tan,Nagy A Habib,Valentí Gomez,Laura Sinigaglia,Joanna Nicholls

doi:10.3390/molecules26216530

Choon Ping Tan, Nagy A Habib + Show 3 more

Open Access

https://doi.org/10.3390/molecules26216530

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Abstract

RNA activation (RNAa) is a mechanism whereby RNA oligos complementary to genomic sequences around the promoter region of genes increase the transcription output of their target gene. Small activating RNA (saRNA) mediate RNAa through interaction with protein co-factors to facilitate RNA polymerase II activity and nucleosome remodeling. As saRNA are small, versatile and safe, they represent a new class of therapeutics that can rescue the downregulation of critical genes in disease settings. This review highlights our current understanding of saRNA biology and describes various examples of how saRNA are successfully used to treat various oncological, neurological and monogenic diseases. MTL-CEBPA, a first-in-class compound that reverses CEBPA downregulation in oncogenic processes using CEBPA-51 saRNA has entered clinical trial for the treatment of hepatocellular carcinoma (HCC). Preclinical models demonstrate that MTL-CEBPA reverses the immunosuppressive effects of myeloid cells and allows for the synergistic enhancement of other anticancer drugs. Encouraging results led to the initiation of a clinical trial combining MTL-CEBPA with a PD-1 inhibitor for treatment of solid tumors.

Highlights

RNA Activation Is a Novel Class of TherapeuticsThe hallmark of healthy cellular function is a well-regulated transcriptional program which expresses the correct dosages of genes at the right space and at the right time
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Years of clinical research on siRNA and ASO has resulted in the approval of drugs that inhibit overexpression of undesirable genes, but there remained a need for treatments that can turn genes back on after downregulation from specific diseases. The solution to this demand presented itself in the mid-2000s when two research groups independently showed that short RNA oligos designed to target the promoter region of several genes increased the transcription of their intended mRNA above basal levels [2,3]

Summary

RNA Activation Is a Novel Class of Therapeutics

The hallmark of healthy cellular function is a well-regulated transcriptional program which expresses the correct dosages of genes at the right space and at the right time. Years of clinical research on siRNA (small interfering RNA) and ASO (antisense oligonucleotide) has resulted in the approval of drugs that inhibit overexpression of undesirable genes, but there remained a need for treatments that can turn genes back on after downregulation from specific diseases. The solution to this demand presented itself in the mid-2000s when two research groups independently showed that short RNA oligos designed to target the promoter region of several genes increased the transcription of their intended mRNA above basal levels [2,3]. Many research groups have reported the success of applying RNAa to their particular disease models and the first drug to utilize RNAa is currently in a clinical trial

Molecular Mechanisms of RNAa

Promising Observations of MTL-CEBPA in Clinical Trials

Findings

Future Perspective for saRNA Therapeutics