Table 1.
Druggable Targets in Sickle Cell Disease
| Therapeutic Target | Rationale | Examples of Potentially Therapeutic Agents |
|---|---|---|
| Synthesis of HbF | Increased HbF is associated with fewer vaso-occlusive episodes and a milder clinical course | • Hydroxyurea • Decitabine • Vorinostat, Panibostat • Pomalidomide • HQK-1001 |
| Synthesis of HbS | Replace synthesis of HbS with either HbF or Hb A, to reduce HbS-related cellular damage | • Hematopoietic stem cell
transplantation • Gene therapy |
| Cell adhesion | Both sickle red cells and leukocytes adhere to each other and to endothelial cells, leading to vaso-occlusion | • SelG1 • PF-04447943 • Rivipansel (GMI-1070) • MST-188 (Poloxamer-188) • Sevuparin • Propranolol • IVIg |
| Inflammation | Sickle red cell interaction with both leukocytes and endothelial cells leads to activation of those cells. In addition, vaso-occlusion results in hypoxia/reperfusion injury and inflammation. | • Regadenoson • NKTT120 • Zileuton • Montelukast • IVIg • Simvastatin |
| Activation of coagulation | Coagulation is chronically activated in SCD and is believed to contribute to vaso-occlusion and organ damage. | • Tinzaparin • Apixaban • Enoxaparin • Unfractionated heparin • N-acetyl cysteine |
| Platelet activation | Platelet activation promotes thrombosis as well as inflammation. | • Ticagrelor • Prasugrel • Eptifibatide • Aspirin |
| Red cell “sickling” | Many agents seek to bind CO to Hb or otherwise increase O2 affinity, in order to reduce HbS gelation | • MP4CO • SCD-101 • Sanguinate (PEG-bHb-CO • AES-103 |
| Red cell dehydration and hemolysis | Red cell dehydration is a contributor to HbS gelation, cell deformation and hemolysis. Some drugs can inhibit the Gardos channel and thus increase cell hydration. | • Clotrimazole • ICA-17043 (senicapoc) |
| Oxidant damage | Anti-oxidant compounds may improve red cell survival and reduce tissue injury. | • L-glutamine • Alpha-lipoic acid • Arginine • omega3 fatty acids • N-acetylcysteine • Nrf2 activators (mono- and di-methylfumarate, sulforaphane) • Haptoglobin • Hemopexin |
| Endothelial damage and vascular biology | Vasculature in SCD shows signs of chronic activation, damage, and remodeling. Abnormal NO availability is thought to contribute. | • Inhaled and intravenous
NO • 6R-BH4 (sapropterin dihydrochloride) • Statins • Bosentan • Losartan • Varespladib • Mg sulfate |