The Small Molecule Syk Inhibitor R788 Inhibits Hematopoiesis and Worsens Anemia in Sickle Cell Disease Mice. Open Access

Syk inhibition with R788 worsened anemia and neutropenia in Townes sickle mice. Non-toxic doses, did not impact NETosis.

R788 treatment reduced splenomegaly in Townes sickle mice but suppressed hematopoiesis leading to neutropenia and worsened anemia.

Vaso-occlusive crises (VOC), thrombosis, inflammation, and immune dysregulation contribute to organ damage and poor outcomes in sickle cell disease (SCD). Since neutrophils and dysregulated extracellular trap formation (NETosis) contribute to sickle pathophysiology, and the spleen tyrosine kinase (Syk) signaling pathway is a key driver of NETosis, we investigated the effect of targeting Syk with fostamatinib (R788). Specifically, we studied the effect of a selective Syk inhibitor R788 on hematologic and biochemical parameters, NETosis, platelet P-selectin expression and platelet-neutrophil aggregate formation in Townes sickle mice at baseline and following exposure to pathophysiological stressors (TNF-α and hypoxia-reoxygenation). Our results showed that at baseline R788 impaired hematopoiesis, and worsened anemia and neutropenia in sickle mice. Additionally, R788 at non-toxic doses had little, if any effect on NETosis, and platelet activation induced by TNF-α or hypoxia-reoxygenation. Severe anemia and neutropenia induced by R788 in the sickle mouse model suggests that concomitant use of Syk inhibitors with hydroxyurea in patients with SCD should be approached cautiously. Further research is required to clarify the benefits and risks of selective Syk inhibition in SCD and other hemolytic conditions exhibiting stress hematopoiesis.

Explanation of Novelty:

This is the first study to demonstrate that Syk inhibition with R788 suppresses hematopoiesis resulting in worsening anemia and neutropenia in Townes sickle mice. Moreover, R788-mediated inhibition of Syk signaling at non-toxic doses (those that do not suppress hematopoiesis) did not adequately suppress NETosis activated by TNF-α or hypoxia-reoxygenation. These findings warrant a cautious approach to targeting Syk signaling in SCD.