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Exploring the Role of shRNAs in Biology and Medicine

Discover the significant impact of short hairpin RNAs (shRNAs) in biology and medicine, from their invention in the early 2000s to their application in large-scale screens and in vivo studies. Explore the challenges and potential of shRNAs, including the need for validation, controlling off-target effects, and viral delivery methods for therapeutic applications. Learn about the progress in clinical trials with shRNAs compared to siRNA and the promising future of shRNA therapeutics.

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Exploring the Role of shRNAs in Biology and Medicine

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  1. Short hairpin RNAs Dave Lyons May 2009

  2. Short hairpin RNAs • Discovery of interfering RNAs • shRNAs in biology • shRNAs in medicine

  3. Short hairpin RNAs • Discovery of interfering RNAs • shRNAs in biology • shRNAs in medicine

  4. Discovery of RNAi . . . 1990 2000 2010

  5. “Invention” of shRNA 2000 2010 Paddison et al. 2002

  6. “Invention” of shRNA Paddison et al. 2002; Rao et al. 2009

  7. Short hairpin RNAs • Discovery of interfering RNAs • shRNAs in biology • shRNAs in medicine

  8. shRNA in biological research • Large-scale screens • In vivo studies • Validation

  9. shRNAs for large-scale screens Dykxhoorn and Lieberman 2005

  10. 2.) Transplantation of infected SCs 3.) Infect mouse with vector shRNAs for in vivo studies 1.) Mouse KO / KI / BAC Dykxhoorn and Lieberman 2005

  11. Pol III promoter Pol II promoter shRNAs for in vivo studies 4.) Tail vein injection Dykxhoorn and Lieberman 2005; Giering et al. 2008

  12. shRNA - validation 4.) Tail vein injection Off-target effects? Pol III promoter Pol III promoter Pol II promoter Pol II promoter Dykxhoorn and Lieberman 2005; Giering et al. 2008

  13. shRNA - validation 1.) need a phenotypic assay to accurately confirm on-target effect. 2.) need to control for specific and non-specific off-target effects. - expression profiling of transfected controls - general immune response? - bottleneck effects (e.g. nuclear export)

  14. Short hairpin RNAs • Discovery of interfering RNAs • shRNAs in biology • shRNAs in medicine

  15. shRNA in medicine • shRNA is difficult to deliver without viruses but in vivo experiments in mouse suggest better overall for specificity than siRNA. • Successful viral targeting is central to future of shRNA therapeutics. • Clinical trials with siRNA outnumber shRNA currently.

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