ALK2 IS A POTENTIAL THERAPEUTIC TARGET IN ANEMIA RESULTING FROM CHRONIC INFLAMMATION
EHA Library. Backus T. 06/09/21; 325597; EP839
Thomas Backus
Contributions
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.
Background:
Hepcidin, a master iron regulator that helps to maintain appropriate iron levels in circulation, is elevated in many diseases of chronic inflammation. Hepcidin is expressed, in part, in response to signaling through activation of the TGF-b type-1 receptor ALK2 and acts to reduce iron export through ferroportin. We have previously demonstrated the effect of inhibiting ALK2 via either a small-molecule or biologic in iron refractory iron deficiency anemia (IRIDA), a genetic form of anemia that results from high hepcidin, in preclinical studies. In IRIDA, KTI-2338, a selective small molecule ALK2 inhibitor, decreased hepcidin and increased serum iron levels in an in vivo mouse model. Hepcidin is also increased in response to elevated IL-6 in chronic inflammation, resulting in secondary anemia of inflammation (AI) in chronic inflammatory diseases such as chronic kidney disease (CKD). Herein, we assessed the therapeutic potential of inhibiting ALK2 signaling on anemia arising from chronic inflammation and determined the effect of modulating BMP signaling in anemia resulting from IL6 and high hepcidin.
Methods:
To assess the role of ALK2 signaling in AI, we evaluated an adenine-induced model of CKD. Briefly, to induce CKD, C57BL/6 mice were dosed daily via PO administration with 50 mg/kg of adenine or vehicle. After 6 weeks of adenine administration, anemia was confirmed in subset of mice. Concomitantly, the remainder of CKD mice began dosing with either vehicle or KTI-2338 5 mg/kg PO daily while continuing to receive daily adenine for 10 days. The study was terminated at 52 days and hematology, serum hepcidin, and serum iron levels were assessed.
Results:
6 weeks of adenine administration led to iron deficiency anemia (37.6% decrease in serum iron) and was associated with increased circulating IL6 (2.42-fold) and hepcidin (3.49-fold). After 10 days of therapy, the vehicle treated group remained anemic with reduced circulating iron, red blood cell (RBC) count, hemoglobin (HGB) and hematocrit (HCT) compared to the controls not receiving adenine. In contrast, mice that were administered KTI-2338 had an increase in serum iron (2.09-fold) and improvements in RBC count, HGB and HCT compared to the vehicle cohort. Reticulocyte HGB content, a measure of the incorporation of iron into hemoglobin, normalized to baseline levels with KTI-2338 therapy. Given that reticulocytes are immature RBCs, the effect on reticulocyte HGB content is potentially predictive that RBC and HGB levels would also continue to increase over a longer time course.
Summary/Conclusion:
We have characterized an established mouse model of chronic inflammatory disease, CKD, as a well-defined model of anemia of inflammation. This preclinical model recapitulates the high IL6 and hepcidin and decreased serum iron that characterizes clinical AI. In this proof-of-concept study, inhibition of ALK2 improved hematological markers of anemia, serum hepcidin, and serum iron levels in a mouse model of anemia of inflammation (AI) resulting from chronic kidney disease characterized by elevated IL6. Inhibition of BMP6 signaling alone can override iron deficiency anemias driven by inflammatory signaling, potentially substantiating that inhibitors targeting ALK2 may provide a viable therapeutic intervention for AI.
Keywords:Anemia, Hepcidin, Iron deficiency anemia, Iron metabolism
Abstract: EP839
Type: E-Poster Presentation
Session title: Iron metabolism, deficiency and overload
Background:
Hepcidin, a master iron regulator that helps to maintain appropriate iron levels in circulation, is elevated in many diseases of chronic inflammation. Hepcidin is expressed, in part, in response to signaling through activation of the TGF-b type-1 receptor ALK2 and acts to reduce iron export through ferroportin. We have previously demonstrated the effect of inhibiting ALK2 via either a small-molecule or biologic in iron refractory iron deficiency anemia (IRIDA), a genetic form of anemia that results from high hepcidin, in preclinical studies. In IRIDA, KTI-2338, a selective small molecule ALK2 inhibitor, decreased hepcidin and increased serum iron levels in an in vivo mouse model. Hepcidin is also increased in response to elevated IL-6 in chronic inflammation, resulting in secondary anemia of inflammation (AI) in chronic inflammatory diseases such as chronic kidney disease (CKD). Herein, we assessed the therapeutic potential of inhibiting ALK2 signaling on anemia arising from chronic inflammation and determined the effect of modulating BMP signaling in anemia resulting from IL6 and high hepcidin.
Methods:
To assess the role of ALK2 signaling in AI, we evaluated an adenine-induced model of CKD. Briefly, to induce CKD, C57BL/6 mice were dosed daily via PO administration with 50 mg/kg of adenine or vehicle. After 6 weeks of adenine administration, anemia was confirmed in subset of mice. Concomitantly, the remainder of CKD mice began dosing with either vehicle or KTI-2338 5 mg/kg PO daily while continuing to receive daily adenine for 10 days. The study was terminated at 52 days and hematology, serum hepcidin, and serum iron levels were assessed.
Results:
6 weeks of adenine administration led to iron deficiency anemia (37.6% decrease in serum iron) and was associated with increased circulating IL6 (2.42-fold) and hepcidin (3.49-fold). After 10 days of therapy, the vehicle treated group remained anemic with reduced circulating iron, red blood cell (RBC) count, hemoglobin (HGB) and hematocrit (HCT) compared to the controls not receiving adenine. In contrast, mice that were administered KTI-2338 had an increase in serum iron (2.09-fold) and improvements in RBC count, HGB and HCT compared to the vehicle cohort. Reticulocyte HGB content, a measure of the incorporation of iron into hemoglobin, normalized to baseline levels with KTI-2338 therapy. Given that reticulocytes are immature RBCs, the effect on reticulocyte HGB content is potentially predictive that RBC and HGB levels would also continue to increase over a longer time course.
Summary/Conclusion:
We have characterized an established mouse model of chronic inflammatory disease, CKD, as a well-defined model of anemia of inflammation. This preclinical model recapitulates the high IL6 and hepcidin and decreased serum iron that characterizes clinical AI. In this proof-of-concept study, inhibition of ALK2 improved hematological markers of anemia, serum hepcidin, and serum iron levels in a mouse model of anemia of inflammation (AI) resulting from chronic kidney disease characterized by elevated IL6. Inhibition of BMP6 signaling alone can override iron deficiency anemias driven by inflammatory signaling, potentially substantiating that inhibitors targeting ALK2 may provide a viable therapeutic intervention for AI.
Keywords:Anemia, Hepcidin, Iron deficiency anemia, Iron metabolism
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.
Background:
Hepcidin, a master iron regulator that helps to maintain appropriate iron levels in circulation, is elevated in many diseases of chronic inflammation. Hepcidin is expressed, in part, in response to signaling through activation of the TGF-b type-1 receptor ALK2 and acts to reduce iron export through ferroportin. We have previously demonstrated the effect of inhibiting ALK2 via either a small-molecule or biologic in iron refractory iron deficiency anemia (IRIDA), a genetic form of anemia that results from high hepcidin, in preclinical studies. In IRIDA, KTI-2338, a selective small molecule ALK2 inhibitor, decreased hepcidin and increased serum iron levels in an in vivo mouse model. Hepcidin is also increased in response to elevated IL-6 in chronic inflammation, resulting in secondary anemia of inflammation (AI) in chronic inflammatory diseases such as chronic kidney disease (CKD). Herein, we assessed the therapeutic potential of inhibiting ALK2 signaling on anemia arising from chronic inflammation and determined the effect of modulating BMP signaling in anemia resulting from IL6 and high hepcidin.
Methods:
To assess the role of ALK2 signaling in AI, we evaluated an adenine-induced model of CKD. Briefly, to induce CKD, C57BL/6 mice were dosed daily via PO administration with 50 mg/kg of adenine or vehicle. After 6 weeks of adenine administration, anemia was confirmed in subset of mice. Concomitantly, the remainder of CKD mice began dosing with either vehicle or KTI-2338 5 mg/kg PO daily while continuing to receive daily adenine for 10 days. The study was terminated at 52 days and hematology, serum hepcidin, and serum iron levels were assessed.
Results:
6 weeks of adenine administration led to iron deficiency anemia (37.6% decrease in serum iron) and was associated with increased circulating IL6 (2.42-fold) and hepcidin (3.49-fold). After 10 days of therapy, the vehicle treated group remained anemic with reduced circulating iron, red blood cell (RBC) count, hemoglobin (HGB) and hematocrit (HCT) compared to the controls not receiving adenine. In contrast, mice that were administered KTI-2338 had an increase in serum iron (2.09-fold) and improvements in RBC count, HGB and HCT compared to the vehicle cohort. Reticulocyte HGB content, a measure of the incorporation of iron into hemoglobin, normalized to baseline levels with KTI-2338 therapy. Given that reticulocytes are immature RBCs, the effect on reticulocyte HGB content is potentially predictive that RBC and HGB levels would also continue to increase over a longer time course.
Summary/Conclusion:
We have characterized an established mouse model of chronic inflammatory disease, CKD, as a well-defined model of anemia of inflammation. This preclinical model recapitulates the high IL6 and hepcidin and decreased serum iron that characterizes clinical AI. In this proof-of-concept study, inhibition of ALK2 improved hematological markers of anemia, serum hepcidin, and serum iron levels in a mouse model of anemia of inflammation (AI) resulting from chronic kidney disease characterized by elevated IL6. Inhibition of BMP6 signaling alone can override iron deficiency anemias driven by inflammatory signaling, potentially substantiating that inhibitors targeting ALK2 may provide a viable therapeutic intervention for AI.
Keywords:Anemia, Hepcidin, Iron deficiency anemia, Iron metabolism
Abstract: EP839
Type: E-Poster Presentation
Session title: Iron metabolism, deficiency and overload
Background:
Hepcidin, a master iron regulator that helps to maintain appropriate iron levels in circulation, is elevated in many diseases of chronic inflammation. Hepcidin is expressed, in part, in response to signaling through activation of the TGF-b type-1 receptor ALK2 and acts to reduce iron export through ferroportin. We have previously demonstrated the effect of inhibiting ALK2 via either a small-molecule or biologic in iron refractory iron deficiency anemia (IRIDA), a genetic form of anemia that results from high hepcidin, in preclinical studies. In IRIDA, KTI-2338, a selective small molecule ALK2 inhibitor, decreased hepcidin and increased serum iron levels in an in vivo mouse model. Hepcidin is also increased in response to elevated IL-6 in chronic inflammation, resulting in secondary anemia of inflammation (AI) in chronic inflammatory diseases such as chronic kidney disease (CKD). Herein, we assessed the therapeutic potential of inhibiting ALK2 signaling on anemia arising from chronic inflammation and determined the effect of modulating BMP signaling in anemia resulting from IL6 and high hepcidin.
Methods:
To assess the role of ALK2 signaling in AI, we evaluated an adenine-induced model of CKD. Briefly, to induce CKD, C57BL/6 mice were dosed daily via PO administration with 50 mg/kg of adenine or vehicle. After 6 weeks of adenine administration, anemia was confirmed in subset of mice. Concomitantly, the remainder of CKD mice began dosing with either vehicle or KTI-2338 5 mg/kg PO daily while continuing to receive daily adenine for 10 days. The study was terminated at 52 days and hematology, serum hepcidin, and serum iron levels were assessed.
Results:
6 weeks of adenine administration led to iron deficiency anemia (37.6% decrease in serum iron) and was associated with increased circulating IL6 (2.42-fold) and hepcidin (3.49-fold). After 10 days of therapy, the vehicle treated group remained anemic with reduced circulating iron, red blood cell (RBC) count, hemoglobin (HGB) and hematocrit (HCT) compared to the controls not receiving adenine. In contrast, mice that were administered KTI-2338 had an increase in serum iron (2.09-fold) and improvements in RBC count, HGB and HCT compared to the vehicle cohort. Reticulocyte HGB content, a measure of the incorporation of iron into hemoglobin, normalized to baseline levels with KTI-2338 therapy. Given that reticulocytes are immature RBCs, the effect on reticulocyte HGB content is potentially predictive that RBC and HGB levels would also continue to increase over a longer time course.
Summary/Conclusion:
We have characterized an established mouse model of chronic inflammatory disease, CKD, as a well-defined model of anemia of inflammation. This preclinical model recapitulates the high IL6 and hepcidin and decreased serum iron that characterizes clinical AI. In this proof-of-concept study, inhibition of ALK2 improved hematological markers of anemia, serum hepcidin, and serum iron levels in a mouse model of anemia of inflammation (AI) resulting from chronic kidney disease characterized by elevated IL6. Inhibition of BMP6 signaling alone can override iron deficiency anemias driven by inflammatory signaling, potentially substantiating that inhibitors targeting ALK2 may provide a viable therapeutic intervention for AI.
Keywords:Anemia, Hepcidin, Iron deficiency anemia, Iron metabolism
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