Overview of Gene Inhibition Therapy

An overview of how gene inhibition therapy works and the main components of RNA interference that result in the inhibition of gene expression.


What Is Gene Inhibition Therapy?

  • Gene inhibition is a therapeutic approach that involves deactivating or “silencing” the expression of a mutated gene that is not functioning properly1–3
  • Gene inhibition works by preventing gene expression at the post-transcriptional level1,4
  • Some genetic diseases are caused
    by a mutated gene that leads to the production of mutant proteins, or “toxic overexpression” of required proteins1,5
  • Gene inhibition involves the introduction of a gene silencer targeting this mutant messenger RNA (mRNA), which stops production of the disease-causing protein, correcting its toxic effect1

Other Approaches for Gene Silencing

Inhibition of gene expression at the post-transcriptional level can also be induced by delivery of antisense oligonucleotides or small interfering RNA (siRNA)1,6

Antisense oligonucleotides are synthetic, short, single-stranded DNA or RNA molecules that interact with mRNA through base pairing to prevent translation of a targeted gene7

siRNAs are short, double-stranded RNA molecules that target complementary mRNA for degradation7,8

Neither of these are gene therapy approaches and therefore will not be the main focus of this module9-11

Gene Inhibition Strategies


Strategies based on the naturally occurring RNA interference (RNAi) process have seen a high level of clinical development due to their potency for inhibiting gene expression12,13

The use of RNA-targeting enzymes such as Cas13 can be utilized for gene knockdown at the RNA level14


Some strategies are based on the use of clustered regularly interspaced short palindromic repeat (CRISPR) genome-editing technologies, which can be adapted to silence gene expression12,14

The CRISPR system is mediated by the CRISPR-associated (Cas) proteins, and CRISPR-Cas uses a guide RNA to specifically recognize the target DNA or RNA sequence12,15

Other Strategies

Other novel strategies to silence gene expression are being investigated12,13

CRISPR interference can be achieved by fusing a nuclease-deactivated Cas protein to a transcriptional inhibitor and targeting it to a transcriptional start site, leading to repression of transcription at the DNA level15

This module with focus on RNAi-based strategies due to the level of clinical development in this field.

Overview of RNAi

RNAi is defined as the sequence-specific “post-transcriptional inhibition” of gene expression mediated by small double-stranded RNAs4

It is a naturally occurring process used by cells to regulate gene expression4,16

Specifically, RNAi involves a series of cellular mechanisms used to prevent genes from being translated into proteins4,16

In addition to regulating gene expression, RNAi is part of the innate immune system and acts as a defense mechanism against bacteria and viral nucleic acids16–18


The mechanism of RNAi was first reported by Fire and Mello in 199819, for which they were awarded the Nobel Prize in Physiology or Medicine 200620.

Triggers of RNAi

RNAi is triggered by double-stranded RNAs, which can be6,16,18,21:

Endogenously generated by cellular genes


Exogenously delivered into the cell either by infecting pathogens or by vectors


While RNAi is a naturally occurring process, therapeutic strategies based on RNAi are being investigated to help treat diseases22


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  2. Strachan T, Read AP. Genetic approaches to treating disease: In: Human Molecular Genetics. 5th ed. Florida: CRC Press, 2018:696–699.
  3. National Center for Biotechnology Information. Gene silencing. Available at: https://www.ncbi.nlm.nih.gov/probe/docs/applsilencing/. Accessed January 30, 2020.
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  11. U.S. FDA. Approved Cellular and Gene Therapy Products. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products. Accessed March 27, 2020.
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  20. The Nobel Prize. Advanced information: RNA interference. Available at: https://www.nobelprize.org/prizes/medicine/2006/advanced-information/. Accessed March 31, 2020.
  21. Lam JK, et al. Mol Ther Nucleic Acids 2015;4:e252.
  22. Pushparaj PN, et al. J Dent Res 2008;87(11):992–1003.