Cell culture and animal models to screen for promising fetal hemoglobin-stimulating compounds

Sickle cell anemia (SCA) and the thalassemias are globally the most common class of inherited single-gene disorders. Current treatment options are limited, especially in developing countries. More practical and cheaper therapies are urgently needed. Since high fetal hemoglobin (HbF) levels ameliorate the clinical symptoms of these diseases, one current approach is to use pharmacological agents to reactivate the gamma-globin genes and stimulate the production of HbF. Several in vitro and in vivo experimental models developed for this purpose are the subject of this review. The models include in vitro established erythroid-like cell lines and primary cultures (both in semisolid and liquid media) of erythroid progenitor cells obtained from normal donors and patients with SCA and beta-thalassemia, as well as in vivo models in genetically modified (transgenic) and unmodified animals. These experimental systems are useful for large-scale screening of compounds for HbF-stimulating potential, for determining the mechanism of action of potent compounds at the cellular and molecular levels, and for studying the pharmacology, pharmacokinetics, and toxicology of the drugs. These models are essential to find, test, and develop new drugs that will be effective and safe for clinical use in adults and children.