Deciphering the role of kielin/chordin-like protein in hepcidin regulation and its relevance in Juvenile Hemochromatosis 2A

This project has been approved for funding - the activation procedure is still pending

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2023

Hereditary Hemochromatosis (HH) is a genetically heterogeneous disease characterized by iron-overload due to decreased hepcidin, a liver hormone that controls body iron levels. When hepcidin  is impaired, as in HH, iron accumulates in various organs, causing toxicity. HH can be classified as juvenile- and adult-HH. Juvenile-HH, such as Juvenile-Hemochromatosis-Type-2A (JH-2A), cause a severe disease that, if untreated, can lead to death. Treatment is symptomatic and consists in phlebotomy. Unfortunately, the treatment is not applicable in all patients and does not correct the primary defect, namely hepcidin deficiency. Therefore, a new therapeutic approach is needed.

Hepcidin is controlled by the BMP-SMAD-pathway. In JH-2A, the disease is due to mutations in HJV, a crucial protein in liver BMP-SMAD pathway.

We have identified the Tdark kielin/chordin like protein (KCP) as a potential new hepatic hepcidin activator that can compensate for the lack of HJV function in JH-2A.

This hypothesis will be tested in cells and in the JH-2A mouse model. Since there is no drug capable of upregulating hepcidin in JH-2A, we will also evaluate EMA-approved drugs for their ability to increase KCP function in the liver. This drug will be tested in a mouse model of JH-2A. Identifying a drug capable of upregulating hepcidin in the liver may be a therapeutic option for those patients who cannot be treated with phlebotomy. In addition, this drug may be of benefit to other patients characterized by iron overload due to low hepcidin production, such as patients affected by beta-thalassemia and other “iron loading anemias”.