Advancements in Sickle Cell Disease Therapy: The Role of a Potent and Selective PDE9 Inhibitor

Hydroxyurea, a medication used for treating sickle cell disease (SCD), raises cGMP levels which in turn boosts fetal hemoglobin in red blood cells, potentially reducing disease severity. However, its side effects, such as infertility and infection susceptibility, are a concern. Phosphodiesterase-9 inhibitors (PDE9i) are being considered as an alternative due to their cGMP-increasing properties. IMR-687 is a PDE9i that is being developed specifically for SCD, avoiding the drawbacks of Hydroxyurea and other PDE9 inhibitors.

Our hypothesis was that PDE9 inhibitors would elevate cGMP in blood-forming cells, enhance fetal hemoglobin in red blood cells, prevent sickling, and reduce inflammation and blood vessel blockage in SCD mouse models. IMR-687 was found to be a potent PDE9A inhibitor, inducing higher cGMP levels than Hydroxyurea at lower concentrations. In a mouse model of SCD, both IMR-687 and Hydroxyurea significantly decreased the percentage of sickled red blood cells and increased fetal hemoglobin levels, along with reducing bilirubin, spleen size, and leucocyte counts.

IMR-687 also showed a significant reduction in blood vessel stasis in sickle mice after oxygen deprivation and resupply. Furthermore, it was confirmed that IMR-687 has low brain penetration, which is beneficial for chronic SCD treatment as it does not affect motor activity or learning and memory in mice.

In conclusion, IMR-687 was found to increase fetal hemoglobin levels and reduce red blood cell sickling, inflammation, and blood vessel stasis without the toxic effects of Hydroxyurea, suggesting it could be a safe, once-daily oral treatment for SCD.