Red blood cell pyruvate kinase properties in Townes and Berkeley sickle cell disease mouse models – Of mice and men

Abstract

Pyruvate kinase (PK), a key ATP-generating enzyme in glycolysis, is a target for novel sickle cell disease (SCD) therapies. Enhancing PK activity lowers 2,3-diphosphyglycerate (2,3-DPG), increases adenosine triphosphate (ATP), and may prevent red blood cell (RBC) sickling. Townes and Berkeley SCD mouse models are commonly used for the development of novel drugs for SCD, but differ from humans in 2,3-DPG and ATP levels, which could be related to underlying differences in PK properties. This study revealed important distinctions with humans (SCD vs healthy controls), such as similar PK/hexokinase (HK) ratios between sickling and non-sickling mouse models and significantly lower PK thermostability in mice. We additionally investigated the effect of a novel RBC PK activator, compound A, on PK properties and sickling tendency in these mice in order to assess SCD mouse model suitability. Results showed that a single dose of compound A led to an increased affinity of PK for phosphoenolpyruvate, a significant increase in PK/HK ratio and a decrease of 2,3-DPG levels. Together, these results offer detailed characterization in the PK properties of two commonly used SCD mouse models, and provide insight into the mode of action of PK activator therapy in SCD mice models.