Sickle cell disease (SCD) is a blood disorder that is passed down through families. About 70,000 Americans and millions around the world are affected by the condition. Red blood cells carry a protein called hemoglobin, which transports oxygen from the lungs to the rest of the body. People with SCD have an abnormal form of hemoglobin that causes red blood cells to become crescent (or sickle) shaped instead of being round. A gene necessary to produce a type of hemoglobin called fetal hemoglobin is turned off. Because of this irregular shape, sickle cells cannot move through blood vessels easily, and they slow blood flow to limbs and organs. This blockage causes pain and organ damage, and it can lead to infection. Fetal hemoglobin is thought to prevent cells from becoming sickle-shaped and blocking blood flow. Currently, no widely available cure exists for SCD. The investigators are developing a drug that can turn the fetal hemoglobin gene back on, allowing the body to produce this type of hemoglobin again. The drug could become a new treatment for SCD.
SCD (a β-globinopathy) results from the homozygous inheritance of an abnormal β-globin gene. The γ-globin gene is necessary for fetal hemoglobin (HbF) production; this gene is silenced during the latter stages of fetal development concurrent with activation of the β-globin gene. A number of scientific, epidemiologic and clinical observations have indicated that increased levels of HbF improve the natural history of SCD and other β-globinopathies by substituting for, or interfering with, the abnormal β-globin gene product. Therefore, a major translational and clinical objective in the preceding 30 years has been to develop effective pharmacologic reversing agents of γ-globin gene silencing. One result of these efforts is the use of hydroxyurea in SCD. However, hydroxyurea only has limited efficacy. A large body of preclinical and clinical evidence indicates that the non-patented cytidine analogue decitabine could be a more effective reactivator of HbF production. Supply, appropriate formulation and toxicology studies of decitabine through BrIDGs will allow important trials in SCD and β-thalassemia to proceed.
Yogen Saunthararajah, M.D.
Public Health Impact
Clinical and epidemiologic observations supported by laboratory studies demonstrating the ability of HbF to interfere with sickle hemoglobin polymerization and prevent sickling — and our understanding of SCD pathophysiology — indicate that effective HbF reactivation remains a worthwhile strategy to treat SCD. Decitabine offers the possibility of even greater and more widespread benefit than the current standard of care, possibly with a similar or better toxicity profile.
The investigator successfully filed an Investigational New Drug (IND) application to the Food and Drug Administration using BrIDGs data and initiated clinical testing.
- Synthesis of Good Manufacturing Practice (GMP) material
- Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies
- IND-directed toxicology
Subchronic Oral Toxicity Study of Decitabine in Combination with Tetrahydrouridine in CD-1 Mice • International Journal of Toxicology • Mar. 17, 2014
Increased CDA Expression/Activity in Males Contributes to Decreased Cytidine Analog Half-Life and Likely Contributes to Worse Outcomes with 5-azacytidine or Decitabine Therapy • Clinical Cancer Research • Feb. 15, 2013
Effects of Tetrahydrouridine on Pharmacokinetics and Pharmacodynamics of Oral Decitabine • Blood • Feb. 2, 2012