Gene Inhibition Therapy

shRNA Versus Artificial miRNA

A summary of the key differences between shRNA and artificial microRNA.

Let’s now summarize the key differences between shRNA and artificial microRNA.

The use of shRNA results in specific gene knockdown and high levels of shRNA expression. This strategy has been used widely because of the simple design, long-term expression, and stability of shRNA. The high levels of shRNAs can potentially oversaturate the endogenous RNAi pathway and result in possible non-specific toxicity. However, structural modifications have been made to address these issues1-5.

In contrast, artificial microRNAs result in less specific gene knockdown and typically lower level of expression. These properties make artificial microRNAs less likely to disrupt endogenous RNAi pathways than shRNAs, which lowers the risk of non-specific toxicity1,2,6.

Because of their simple design and long-term expression and stability, shRNAs have been investigated in a wide variety of applications, including myocardial ischemia, HIV, and tumor growth1,7,8.

Artificial microRNAs have also been investigated in a variety of diseases such as hepatitis B9,10, amyotrophic lateral sclerosis11, facioscapulohumeral muscular dystrophy12, and Huntington’s disease13.

Because all cases of Huntington’s disease are caused by the same basic mutation that results in the accumulation of a mutant protein, it is an ideal target for gene inhibition therapies14. In Huntington’s disease, mutations in the huntingtin or HTT gene lead to a toxic accumulation of the mutant HTT protein in the brain, which causes massive neurodegeneration and clinical symptoms associated with the disease15. By selectively reducing mutant HTT expression, gene inhibition strategies could reverse the pathological features of Huntington’s disease associated with aberrant accumulation of HTT protein15.

This concludes the module on how gene inhibition therapy works.

References

  1. Borel F, et al. Mol Ther 2014;22(4):692–701.
  2. Fowler DK, et al. Nucleic Acids Res 2016;44(5):e48.
  3. Grimm D, et al. Nature 2006;441:537–541.
  4. Ehlert EM, et al. BMC Neurosci 2010;11:20.
  5. Giering JC, et al. Mol Ther 2008;16:1630–1636.
  6. Wu H, et al. PLoS One 2011;6:e28580.
  7. News Medical Life Sciences. Short Hairpin RNA (shRNA) Interference: Therapeutic Applications. Available at: https://www.news-medical.net/life-sciences/Short-Hairpin-RNA-(shRNA)-Interference-Therapeutic-Applications.aspx#Therapeutic%20applications%20of%20shRNA. Accessed March 31, 2020.
  8. Wolstein O, et al. Mol Ther Methods Clin Dev 2014;1:11.
  9. Ahn M, et al. Hum Gene Ther 2011;22(12):1483–1497.
  10. Ma J, et al. PLoS One 2012;7(10):e46096.
  11. Stoica L, et al. Ann Neurol 2016;79(4):687–700.
  12. Wallace LM, et al. Mol Ther 2012;20(7):1417–1423.
  13. Spronck EA, et al. Mol Ther Methods Clin Dev 2019;13:334–343.
  14. Wild EJ, Tabrizi S. Lancet Neurol 2017;16(10):837–847.
  15. Vagner R, et al. Neurol Res Int 2012;2012:358370.