Targeting ALK2 Signaling to Treat Iron Refractory Iron Deficiency Anemia: Insights from a Novel Mouse Model

Hepcidin, a hormone that controls iron levels in the body, is regulated by activin receptor-like kinase 2 (ALK2). ALK2 is activated by BMP6 and hemojuvelin (HJV), but its signaling is inhibited by matriptase-2 (MT-2), which prevents hepcidin production. Iron-refractory iron deficiency anemia (IRIDA) is caused by a lack of functional MT-2, leading to high hepcidin levels, low iron, and anemia.

The study aimed to evaluate the impact of modulating ALK2 activity on hepcidin and iron levels, specifically using KTI-2338, a selective ALK2 inhibitor, in a mouse model of IRIDA. C57BL/6 mice were given KTI-2338 orally for three days at varying doses to determine the effective dose range. Blood samples were taken at different times post-dose to track hepcidin and iron regulation.

An IRIDA mouse model was created using siRNA against TMPRSS6 to deplete MT2. After confirming anemia, the mice were treated with KTI-2338 or a vehicle control. The study concluded that KTI-2338 increased serum iron levels at all tested doses and reduced hepcidin levels at higher doses. The treatment also improved hematological parameters in the IRIDA model, suggesting that ALK2 inhibition could be beneficial for IRIDA patients and other hepcidin-mediated anemias.