Targeting pyruvate kinase in rare anemias: a novel therapeutic strategy

Red blood cells (RBCs) are responsible for oxygen transport throughout the human body, which is necessary for the cellular processes in different tissues. For proper functionality and survival of RBCs, they are dependent on glycolysis, the process that generates energy within RBCs. A key enzyme in glycolysis is pyruvate kinase (PK). The aim of this thesis was to shed light on PK in RBCs of patients with different rare (RBC) disorders.

These disorders are hereditary spherocytosis (HS), hereditary xerocytosis (HX), and the myelodysplastic syndromes (MDS). HS and HX are congenital diseases of the RBC, where RBCs are broken down more rapidly in the spleen, leading to anemia. MDS are a group of acquired bone marrow diseases, occurring more frequently in late adulthood. Patients with MDS suffer from impaired production of RBCs due to bone marrow dysplasia, resulting in anemia. We observe that in all three of these diseases, the enzyme PK is affected in the RBCs. Therefore, we investigated the ex vivo effects of PK activators on the RBCs of these patients. Our results show that the RBCs of all three patient groups respond to PK activation. PK activity increases, resulting in increased energy levels. This also has a beneficial effect on the functionality of the RBCs. This forms the basis for future research into whether these patients may also benefit from taking PK activators as therapeutic drugs.

Additionally, the role of a diagnostic test, namely osmotic gradient ektacytometry, is further explored: this laboratory test may also be of value for understanding the disease mechanism and assessing the disease severity in patients with HS. This is important, as it may allow physicians to extract even more information from a standard diagnostic test.