Sickle cell disease (SCD) affects about 100,000 people in the United States and hundreds of thousands more in Africa and the “malaria belt” worldwide. Homozygosity or compound heterozygosity for a point mutation in the HBB gene causes deoxygenated hemoglobin (Hb) S in red blood cells (RBCs) to stick together and form long stick-like polymers, deforming the cells into sickle shapes. Sickled RBCs occlude capillaries and lyse prematurely, causing episodic severe pain, severe hemolytic anemia, acute and chronic organ damage, disability, and premature death. Although its genetic cause and basic pathophysiology have been understood for decades, research funding and therapeutic progress have been lacking. Treatments remain limited to palliative measures including blood transfusions and opioid pain medications, and hydroxyurea, a repurposed drug that increases fetal hemoglobin (Hb F) synthesis and reduces but does not eliminate disease complications. Curative hematopoietic stem cell transplants are limited by the availability of appropriately matched donors and high toxicity risks. Gene therapy remains technically challenging and available only in highly specialized medical settings. Thus, better treatments are desperately needed.
Oksenberg and colleagues have demonstrated effective prevention of Hb S polymerization with a new small molecule in human Hb S RBCs in vitro and in a mouse model of SCD. The new drug, GBT440, reversibly binds to Hb, preventing the conformation change when Hb is deoxygenated. In the presence of this compound, Hb S polymerization is inhibited, and RBCs retain their normal biconcave shape. In transgenic SCD mice, GBT440 treatment prolonged RBC survival with excellent oral bioavailability and pharmacokinetics that support once-daily dosing. This agent is currently undergoing phase 1/2 human trials.
This compound is one of several proposed new treatments for SCD. Other strategies currently in clinical trials include inhibitors of blood cell interactions with the vascular endothelium and more potent Hb F induction agents. Combination therapy, such as with a Hb F inducer plus an antipolymerization agent, may be even more effective than monotherapy. Hopefully the increased interest in discovering effective treatments for SCD will bring long-needed relief to patients around the world.
D. Oksenberg et al., GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br. J. Haematol. 10.1111/bjh.14214 (2016). [Abstract]
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