Silence Therapeutics PLC · NASDAQ:SLN

Silence Therapeutics — EuroTides 2016

16 slides from Silence Therapeutics's conference presentation, Nov 15, 2016

  1. Slide 1: Hepatic Gene Disruption In Vivo After Liposomal Delivery of Cas9 mRNA and Guide RNAs

    Hepatic Gene Disruption In Vivo After Liposomal Delivery of Cas9 mRNA and Chemically Modified Guide RNAs November 15th, 2016 Adrien Weingaertner, PhD © Silence Therapeutics 2016

  2. Slide 2: Disclaimer

    Disclaimer The information contained in this presentation is being supplied and communicated to you on a confidential basis solely for your information and may not be reproduced, further distributed to any other person or published, in whole or in part, for any purpose. In accordance with the prohib

  3. Slide 3: mRNA Delivery

    mRNA Delivery mRNA lipoplex Target protein Ribosome Target mRNA 3

  4. Slide 4: Our mission: Establish a clinically viable technology platform for therapeutic mRNAs

    Our mission: Establish a clinically viable technology platform for therapeutic mRNAs Delivery system mRNA mRNA lipoplex Vasculature Macrophages Liver 4 © Silence Therapeutics 2016

  5. Slide 5: Technology platform to generate novel delivery systems

    Technology platform to generate novel delivery systems Cationic lipids Physicochemical characterization Helper/ fluorescence PEGylation TNS co lipids 4 5 6 7 8 pH Zeta potential Particle size Intensity Surface charge +/- Ratio 0 -200 -100 0 100 200 30 60 120 240 480 Size (nm) [log] Formulation proce

  6. Slide 6: Screening for biodistribution of functional mRNA delivery in vivo

    lu c ife r a s e a c t iv ity lu c ife r a s e a c t iv ity [ p g /g t is s u e ] [ p g /g t is s u e ] 6 1 10 100 1 000 10 000 100 000 1 000 000 0 1 000 2 000 3 000 CD7907 CD7907 CD7910 CD7910 CD7911 CD7911 CD8902 CD8902 CD8903 CD8903 CD8904 CD8904 CD8906 Feb. 2015 CD8906 CD8908 CD8908 CD8909 CD890

  7. Slide 7: Time course and biodistribution of GN2205 functional luciferase mRNA delivery

    Time course and biodistribution of GN2205 functional luciferase mRNA delivery -19 days 0h 2h 4h 6h 8h 12h 24h 48h IV administration of scid beige 1mg/kg mRNA Hep3B (5x106 cells s.c.) (FLuc; ᴪ; 5MeC; TriLink) ex vivo quantification of luciferase activity (tumor size ~350mm³, in tissue lysates group s

  8. Slide 8: Dose response to GN2205 with hEPO and FLuc mRNA

    Dose response to GN2205 with hEPO and FLuc mRNA 0h 4h IV administration of 1mg/kg mRNA ex vivo quantification of luciferase (FLuc or hEPO; ᴪ & 5MeC; TriLink) activity in tissue lysates or hEPO C57BL/6 (group size: n=6) in EDTA-plasma Luciferase activity 0.03 mg/kg hEPO 100,000 0.1 mg/kg Luciferase a

  9. Slide 9: Topology of the liver

    Topology of the liver 9 © Silence Therapeutics 2016

  10. Slide 10: GN2205 siRNA delivery in the liver

    GN2205 siRNA delivery in the liver 0h 48h h e p a to c y te e n d o t h e lia l c e lls ( T T R - liv e r) ( T ie 2 - liv e r) 1 .5 1 .5 IV administration T T R /a c t i n T ie 2 /a c tin RT-PCR 1 .0 1 .0 0.5 or 1.0 mg/kg quantification 0 .5 0 .5 siRNA (Silence) of transcripts C57BL/6 (n=4-6) 0 .0 0

  11. Slide 11: GN2205 targets vascular cells in liver

    GN2205 targets vascular cells in liver 0h 48h L iv e r S p le e n T ie 2 ( e n d o th e lia l c e lls ) T ie 2 ( e n d o th e lia l c e lls ) IV administration RT-PCR 1 .5 2 .0 0.5 mg/kg siRNA quantification (Silence) 1 .5 of transcripts T ie 2 /a c tin T ie 2 /a c tin 1 .0 C57BL/6 (n=4-6) 1 .0 0 .5

  12. Slide 12: GN2205 RNA delivery platform

    GN2205 RNA delivery platform Liver:  Hepatocytes & hepatocyte precursors  Endothelial cells  Stellate cells  Macrophages  Pericytes x Cholangiocytes Spleen, Lung, heart & kidney : Liver & Spleen x Endothelial cells 12 © Silence Therapeutics 2016

  13. Slide 13: GN2205 co-delivery of guide RNA & spCas9-mRNA

    GN2205 co-delivery of guide RNA & spCas9-mRNA day 1 day 35 day 63 day 91 day 119 day 147 day 175 day 203 IV administration of 1mg/kg and quantification of serum protein at indicated 0.5 mg/kg mRNA & guide RNA time points by standardized ELISA (Cas9-mRNA: ᴪ & 5MeC, TriLink; guide RNA: Silence) c57BL/

  14. Slide 14: Summary

    Summary • Identification of LNP with 100 fold Increased activity in liver • Targeting multiple cell types in the liver • Suitable for different RNA payloads co-delivery of Cas9 mRNA and guide RNA results in long lasting gene disruption 14 © Silence Therapeutics 2016

  15. Slide 15: Acknowledgement

    Acknowledgement Formulation team: Gemma Navarro & Claudine Dojahn siRNA team: Ute Schaeper CRISPR team: Daniel Tondera Vivarium: Birgit Durieux 15 © Silence Therapeutics 2016

  16. Slide 16: Thank you!

    Thank you! 16 © Silence Therapeutics 2016

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