Silence Therapeutics PLC · NASDAQ:SLN
Silence Therapeutics — 14th International Conference on Thalassaemia & Haemoglobinopathies (November 2017)
9 slides from Silence Therapeutics's conference presentation, Nov 19, 2017
Slide 1: Development of a GalNAc-siRNA Conjugate Targeting TMPRSS6 for Treatment of Iron Overload
Development of a GalNAc-siRNA Conjugate Targeting TMPRSS6 for Treatment of Iron Overload Dr. Ute Schaeper Nov 19th 2017
Slide 2: Iron Overload in Thalassemia
Iron Overload in Thalassemia • Mutations in HBB cause “stressed” erythropoiesis, hemolytic anemia & GI hyperabsorption of dietary iron • Blood transfusions further enhance iron overload • High iron levels worsen anemia and enhance dependency on blood transfusions • Tissue accumulation of iron yiel
Slide 3: Rationale for Targeting TMPRSS6
Rationale for Targeting TMPRSS6 > TMPRSS6 is a negative regulator of the BMP/SMAD signaling TMPRSS6 BMP pathway; activation of the pathway induces Hepcidin expression P > Hepcidin reduces uptake of dietary iron and the release of iron from cellular storage Hepcidin P SMAD > Hepcidin levels are low i
Slide 4: GalNAc siRNA Conjugate Inhibits TMPRSS6 Expression in Primary Hepatocytes
GalNAc siRNA Conjugate Inhibits TMPRSS6 Expression in 1° Hepatocytes by Receptor-Mediated Uptake TMPRSS6 mRNA TMPRSS6 mRNA (siRNA screen) (receptor-mediated uptake) 1.5 h Hep3B cells Normalised TMPRSS6 mRNA 1° Hep (mouse) 1° Hep (cyno) 1° Hep (human) Normalised TMPRSS6 mRNA Normalised TMPRSS6 mRNA I
Slide 5: TMPRSS6 siRNA Conjugate is Functional in vivo (Mice)
TMPRSS6 siRNA Conjugate is Functional in vivo (Mice) Study design d1 d4 s.c. n=6 TMPRSS6 mRNA Hepcidin mRNA Iron (Liver) (Liver) (Serum) TMPRSS6/Actin mRNA Serum iron [µmol/L] POM: Silencing of TMPRSS6 in the liver induces Hepcidin expression and lowers serum iron levels in mice
Slide 6: SLN124 Lowers Serum Iron Levels and Modulates Tissue Iron Distribution in Rodent Model
SLN124 Lowers Serum Iron Levels and Modulates Tissue Iron Distribution in Rodent Model for Hereditary Hemochromatosis TMPRSS6 mRNA Hepcidin (Serum) Iron (Serum) HFE-/- mice SLN124 s.c. 2.0 (6-8 wks) n=6-7 1.5 Serum Iron [µg/dl] Hepcidin [ng/ml] Weeks 0 1 2 3 1.0 0.5 *** 0.0 3 mg/kg 1 mg/kg 3mg/kg PB
Slide 7: SLN124 Normalises ROS and Improves RBC Parameters in Thalassemia Intermedia Disease Model
SLN124 Normalises ROS and Improves RBC Parameters in Thalassemia Intermedia Disease Model (Hbbth3/+ Mice) RBCs, Reactive Oxigen Species (ROS) Hbbth3/+ mice SLN124 s.c. (6-8 wks) WT Hbb th3/+ Hbb th3/+ n=3-6 ut Ctr SLN124 Weeks 0 1 2 3 4 5 % Reticulocytes 25 p = 0.0042 20 Prof. J. Vadolas HCT [%] R
Slide 8: Summary & Conclusion
Summary & Conclusion SLN124 a GalNAc siRNA conjugate targeting TMPRSS6 expression in the liver > Highly potent, with durable activity by single s.c. application > Lowers serum iron levels, transferrin saturation and reduces tissue iron accumulation in rodent model of hereditary hemochromatosis > Nor
Slide 9: Acknowledgements
Acknowledgements Heidelberg University Monash Medical Centre/Melbourne S. Dames Prof. M. Muckenthaler Prof. J. Vadolas Dr. K. Löffler Dr. S. Altamura Dr. G. Grigoriadis M. Eisermann Dr. S. Schubert Dr. C. Frauendorf Dr. L. Bethge M. Aleku Dr. U. Zügel