Bridging Pathophysiology and Therapeutic Targets in Sickle Cell Disease

Sickle cell disease (SCD) is a complex, multifactorial genetic disorder characterized by significant clinical variability, ranging from severe childhood complications to relatively mild, symptom-free adulthood. Despite major advances in understanding its molecular mechanisms and developing new therapeutic strategies, effective treatment options for SCD remain limited. This thesis investigated various red blood cell (RBC)-related pathophysiological properties in SCD, their relationship to clinical outcomes, and their potential as therapeutic targets.

In particular, this thesis contributes to a better understanding of the function of pyruvate kinase and its influence on various properties of the red blood cell. Pyruvate kinase is an important enzyme involved in the energy production of red blood cells, and activators of this enzyme are currently being investigated in clinical studies. Our findings demonstrate that pyruvate kinase activity and thermostability are associated with important RBC parameters. Further, decreased pyruvate kinase activity and thermostability are correlated with a higher prevalence of both acute and chronic SCD-related complications, supporting the rationale for pyruvate kinase activation as therapeutic approach.

Additionally, pyruvate kinase properties were compared between SCD mouse models and human samples to assess model suitability for preclinical evaluation. We further examined the differential response of distinct RBC subpopulations, low-density and high-density RBCs, respond to a novel pyruvate kinase activator, exploring potential variability in therapeutic response. Furthermore, incubation with a compound composed of ten amino acids and their derivatives improved RBC functionality, while repetitive phlebotomy, aimed at reducing blood viscosity and inducing iron deficiency, led to measurable improvements in laboratory findings and clinical symptoms. Hopefully, this thesis will stimulate future research into these mechanisms in clinical studies.