Sickle cell disease (CSD) is a hematologic disorder caused by a disease mutation in the adult β-globin gene. CSD and β-thalassemia are the most common inherited disorders in humans. When SCD patients have higher levels of fetal hemoglobin (HbF), it inhibits the formation of the misshaped sickle hemoglobin that are rigid, fragile and die prematurely.
Scientists believe that with the right drug to induce high levels of HbF synthesis in patients with SCD and β-thalassemia, the disorders could be medically managed, improving morbidity and mortality.
Using mice models, these researchers found that forcing elevated levels of the TR2 and TR4 nuclear receptor “orphans” enhanced fetal y-globin gene expression and HbF synthesis in the SCD mice. HbF levels were as much as 24 percent in one TR2/TR4 transgene mouse, compared to a 9.8 percent in an SCD mouse. Compared to the SCD mice, the TR2/TR4 mice showed alleviation of anemia, diminished hemolysis, and reduction of hepatosplenomegaly and liver necrosis and inflammation.
The authors assert, that “therapeutic manipulation of TR2 and/or TR4 activities in SCD patients could lead to persistently elevated HbF synthesis and thus significantly lessen both the underlying cause and the secondary pathologies ascribed to the disease without adverse effects.”