Silence Therapeutics PLC · NASDAQ:SLN
Silence Therapeutics — TIDES: Oligonucleotide and peptide therapeutics 2017
21 slides from Silence Therapeutics's conference presentation, May 2, 2017
Slide 1: Therapeutic RNA delivery
Therapeutic RNA delivery 05/02/2017 – TIDES Dr. Adrien Weingärtner Head of Technology Development
Slide 2: Forward looking statements
Forward looking statements THE INFORMATION CONTAINED IN THIS PRESENTATION IS BEING SUPPLIED AND COMMUNICATED TO YOU ON A CONFIDENTIAL BASIS SOLELY FOR YOU INFORMATION AND MAY NOT BE REPRODUCED, FURTHER DISTRIBUTED TO ANY OTHER PERSON OR PUBLISHED, IN WHOLE OR IN PART, FOR ANY PURPOSE. IN ACCORDANCE
Slide 3: LNP delivery of RNA
LNP delivery of RNA Lipid nanoparticle approach mRNA Gene editing payloads siRNA (CRISPR/Cas9) Vasculature Liver Macrophages 3 © Silence Therapeutics 2017
Slide 4: 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 n=6) r
Slide 5: GN2205 targets multiple cell types in the liver
GN2205 targets multiple cell types in the liver h e p a to c y te e n d o t h e lia l c e lls 0h 48h ( T T R - liv e r) ( T ie 2 - liv e r) 1 .5 1 .5 T T R /a c t i n T ie 2 /a c tin 1 .0 1 .0 IV administration RT-PCR 0 .5 0 .5 0.5 mg/kg siRNA quantification (Silence) 0 .0 0 .0 of transcripts b u ff
Slide 6: GN2205 targets vascular cells of liver only
GN2205 targets vascular cells of liver only 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 1 .5 T ie 2 /a c tin T ie 2 /a c tin 1 .0 (Silence) of transcripts 1 .0 C57BL/6 (n=4-6)
Slide 7: GN2205 RNA delivery platform
GN2205 RNA delivery platform Payloads: mRNA siRNA Liver target cells: Hepatocytes Endothelial cells Stellate cells Macrophages Pericytes x Cholangiocytes The LNP is suitable for RNA payloads and targets multiple liver cell types. 7 © Silence Therapeutics 2017
Slide 8: 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 day 238 day 266 day 294 IV administration of 1mg/kg and quantification of serum protein at indicated 0.5 mg/kg mRNA & guide RNA time points by standardized ELISA & final (Cas9-mRNA: ᴪ & 5MeC, Tr
Slide 9: Summary – LNP delivery approach
Summary – LNP delivery approach We have developed a liver targeting LNP-formulation that targets multiple cell types Our LNP is suitable for efficient delivery of both siRNA and mRNA payloads Co-delivery of Cas9 mRNA and guide RNA results in long lasting gene disruption in vivo 9 © Silence Therapeut
Slide 10: New Focus: siRNA conjugates
New Focus: siRNA conjugates LNP Conjugation approach approach mRNA Gene editing payloads siRNA w/ siRNA GalNAc cluster (CRISPR/Cas9) Vasculature Liver Macrophages Hepatocytes 10 © Silence Therapeutics 2017
Slide 11: Hepatocyte delivery by GalNAc
Hepatocyte delivery by GalNAc Scheme based on information provided by Essentials of Glycobiology. 2nd edition. Varki A, Cummings RD, Esko JD, et al., editors. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. GalNAc linked to siRNA GalNAc binds to a highly expressed ASGP recept
Slide 12: Key considerations for GalNAc-siRNA
Key considerations for GalNAc-siRNA siRNA payload extensively chemically modified • with 2’-O-Me, 2’-F, PS & other • to stabilized against nucleases in biofluids and cytoplasm • to minimize immune stimulation • to improve overall performance (therapeutic window) Linker • with optimized length and st
Slide 13: Knockdown of Target X using GalNAc-siRNA conjugates
Knockdown of Target X using GalNAc-siRNA conjugates In vitro In vivo 0h 24h 0h 48h Murine 1°Hepatocytes RT-PCR s.c. administration RT-PCR GalNAc-siRNA conjugate quantification GalNAc-siRNA conjugate quantification of transcripts c57BL/6 (n=4) of transcripts Target X gene expression 24h post treatmen
Slide 14: Duration of knockdown in mice (2nd vs 3rd gen. GalNAc)
Duration of knockdown in mice (2nd vs 3rd gen. GalNAc) day 0 day 7 day 14 day 21 day 28 2nd & 3rd gen. GalNAc- RT-PCR siRNA, s.c., 2 mg/kg quantification c57BL/6 (n=4) of transcripts 1,5 Duration of Knockdown: 2nd vs 3rd generation GalNAc (mean ± SD, knockdown in %) Target Y / PTEN -15% -13% 1,0 -40
Slide 15: Dose Response to GalNAc-siRNA (3rd gen) in mice
Dose Response to GalNAc-siRNA (3rd gen) in mice 0h 48h 3rd gen. GalNAc-siRNA, RT-PCR s.c., 0.1 to 3 mg/kg quantification c57BL/6 (n=4) of transcripts Target gene expression in mouse liver 48h post s.c. application of 1,5 indicated dose (mean ± SD, knock down in %) -5% Target Y / PTEN 1,0 -32% 0,5 -7
Slide 16: Long-lasting knockdown with 3rd gen. GalNAc siRNA conjugates in NHP
Long-lasting knockdown with 3rd gen. GalNAc siRNA conjugates in NHP day -7 day 0 day 4 day 7 day 14 ..weekly.. day 84 day 91 s.c. administration of 3rd gen. quantification of serum protein Target Y at GalNAc-siRNA,1 and 0.3 mg/kg indicated time points (n=4) Duration and dose response of knockdown
Slide 17: Safety parameters of 3rd generation GalNAc conjugate in NHP
Safety parameters of 3rd generation GalNAc conjugate in NHP Changes in cytokine levels expressed as fold (×) of the predose group mean values GalNAc-Target Y GalNAc-control Cytokine 0.3 mg/kg b.w. 1.0 mg/kg b.w. 1.0 mg/kg b.w. males females males females males females IL-7 3 none none 2 none none 2
Slide 18: Our pipeline
Our pipeline Our programmes Out-licensed programmes (AtuRNAiTM) 18 © Silence Therapeutics 2017
Slide 19: Summary – GalNAc conjugates
Summary – GalNAc conjugates Progress made in our new focus area: • Improved GalNAc linker results in increased potency and duration of effect • GalNAc-siRNA conjugates successfully translated from mouse to NHP • Well tolerated in all species tested • Established a GalNAc-siRNA based pipeline across
Slide 20: Acknowledgements
Acknowledgements Silence Berlin & London Team 20 © Silence Therapeutics 2017
Slide 21: Thank you!
Thank you! +} SILENCE THERAPEUTICS
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