Exploring metabolic dysregulation and therapeutic targets in sickle cell disease and rare hereditary red blood cell disorders

Summary

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Hereditary red blood cell (RBC) disorders are genetically and phenotypically heterogenous disorders that may all impact RBC metabolism to a variable extent. Hereditary hemolytic anemias including sickle cell disease (SCD) represent a substantial part of all anemias. In general, the burden of disease and disability caused by anemias is underestimated. Although the prevalence of SCD is high in some low- and middle-income regions, it is considered a rare disease in the Netherlands and other high-income regions. Since in high-income regions most research is conducted on more prevalent diseases, patients with SCD still face significant challenges in managing their symptoms. Nowadays, great advances have been made and more attention is paid to research that focuses on SCD. This has provided new insights on how dysregulated RBC metabolism may be involved and targeted in SCD and other, rare hereditary RBC disorders.

The aims of this thesis were to improve the knowledge about potential emerging therapies that target RBC metabolism in SCD and to study new pathologic variants of other, rare hereditary RBC disorders associated with dysregulated RBC metabolism. This thesis in particular describes studies on two novel, RBC function-improving therapies in development for SCD. SCD thus serves as a use case for a better understanding of dysregulated RBC metabolism in two other, rare hereditary RBC disorders that were identified, studied and described in this thesis.

The efficacy of therapies that modulate RBC metabolism in SCD including the oral pyruvate kinase (PK) activator mitapivat and a composition of endogenous metabolic modulators is elaborated in Part I of this thesis. Overall, we conclude that targeting RBC metabolism in SCD is promising as a novel therapeutic approach.
In Part II of this thesis, new interesting insights into dysregulated RBC metabolism of novel variants associated with extremely rare hereditary RBC disorders are given. Cases of congenital erythrocytosis associated with heterozygosity for bisphosphoglycerate mutase (BPGM) variants and hereditary hemolytic anemia in a patient with hemizygosity for a novel variant in Adenosine Triphosphatase Phospholipid Transporting 11C (ATP11C) are described. More awareness is created on identifying novel variants in genes involved in RBC metabolism. Hopefully, these cases stimulate future research to gather further functional evidence to relate genotypes to phenotypes in the heterogenous group of hereditary RBC disorders.