DEVELOPMENT OF A GALNAC SIRNA CONJUGATE TARGETING TMPRSS6 FOR THE TREATMENT OF IRON OVERLOAD DISORDERS, SUCH AS B-THALASSEMIA
Author(s): ,
Ute Schaeper
Affiliations:
Drug Discovery,Silence Therapeutics GmbH,Berlin,Germany
,
Sandro Altamura
Affiliations:
Molecular Medicine,University of Heidelberg,Heidelberg,Germany
,
Sibylle Dames
Affiliations:
Drug Discovery,Silence Therapeutics GmbH,Berlin,Germany
,
Steffen Schubert
Affiliations:
Drug Discovery,Silence Therapeutics GmbH,Berlin,Germany
,
Christian Frauendorf
Affiliations:
Chemistry Manufacturing Controls,Silence Therapeutics GmbH,Berlin,Germany
,
Manuela Aleku
Affiliations:
Non Clinical Development,Silence Therapeutics GmbH,Berlin,Germany
,
Martina Muckenthaler
Affiliations:
Molecular Medicine,University of Heidelberg,Heidelberg,Germany
,
George Grigoriadis
Affiliations:
Centre for Cancer Research,Hudson Institute of Medical Research,Melbourne,Australia
,
Jim Vadolas
Affiliations:
Centre for Cancer Research,Hudson Institute of Medical Research,Melbourne,Australia
Ulrich Zügel
Affiliations:
Drug Discovery,Silence Therapeutics GmbH,Berlin,Germany
EHA Library. Schaeper U. 06/16/18; 214565; S893
Ute Schaeper
Ute Schaeper
Contributions
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Abstract

Abstract: S893

Type: Oral Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 16:30 - 16:45

Location: Room A13

Background
Hyperferremia is a major health problem in hemochromatosis, thalassemia and sickle cell anemia.  Severe symptoms of excess iron can lead to liver cirrhosis, diabetes, and heart failure.  In hereditary hemochromatosis, gene mutations in the hepcidin-ferroportin axis controlling iron homeostasis, lead to hepatic iron overload.  In thalassemia major patients, iron overload develops as a consequence of frequent blood transfusions to ameliorate severe anemia.  In addition, iron overload develops in patients with b-thalassemia intermedia, due to gastrointestinal iron hyperabsorption.  Thus, in both indications iron overload is caused by dysregulation or dysfunction of the hepcidin-ferroportin axis.  Importantly, expression of the peptide hormone hepcidin, which is the key player in iron homeostasis, is abnormally low and unable to block ferroportin-mediated intestinal iron absorption.  Hepcidin is predominantly produced by the liver and is induced by activation of the BMP/SMAD signalling pathway.  Hepcidin is furthermore under the negative control of the transmembrane protease matriptase 2, encoded by the TMPRSS6 gene.

RNA interference is a powerful technology for inhibiting the expression of disease associated targets.  Silence Therapeutics has developed siRNA conjugate technology for the selective inhibition of target gene expression in the liver.  siRNAs conjugated to a GalNAc ligand bind efficiently to the asialoglycoprotein (ASGP) receptor expressed predominantly by hepatocytes.  Thereby they provide a safe and efficient delivery technology for targeting disease modifying genes in the liver for therapeutic purposes.

Here we report on the identification and pharmacological evaluation of SLN124, a GalNAc-siRNA conjugate targeting TMPRSS6 expression, for the treatment of iron overload disorders, such as b-thalassemia.  Moreover, this study demonstrates that our GalNAc-conjugated siRNAs provide a safe and efficient delivery system and hold great promise for the targeted knock-down of modifier gene expression in the liver for therapy.

Aims
Identification and characterization of SLN124, a GalNAc-siRNA conjugate targeting TMPRSS6 expression, for treatment of b-thalassemia and iron overload.

Methods
Lead identification and pharmacological characterization of siRNA conjugates in cell based assays, in rodent disease models and in non-human primates.

Results
We will present the identification and pharmacological characterization of SLN124, the GalNAc-siRNA conjugate targeting TMPRSS6 expression.  A single subcutaneous administration is sufficient to achieve significant modulation of target gene expression in mice and in non-human primates over several weeks.  SLN124 reduces systemic iron levels, transferrin saturation and tissue iron levels in rodent models for hereditary hemochromatosis.  In addition, we show the therapeutic efficacy of SLN124 in an animal model for b-thalassemia intermedia on erythropoiesis and anemia.  Safety and tolerability are assessed in relevant preclinical models.  SLN124 shows dose-dependent and long-lasting effects on target expression as well as on modulation of iron stores and normalization of erythropoiesis in b-thalassemia mice and was well tolerated. 

Conclusion
GalNAc-siRNA conjugate SLN124 is a promising candidate for treatment of iron overload and anemia in b-thalassemia and related disorders.  SLN124 is in preclinical development and we plan to enter clinical development by end of 2018.

Session topic: 30. Iron metabolism, deficiency and overload

Keyword(s): Anemia, Erythropoieisis, iron overload, Thalassemia

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