Study of Decitabine and Tetrahydrouridine (THU) in Patients With Sickle Cell Disease

Inclusion Criteria: * Age 18 years or older. * Written, informed consent provided by the subject before study entry. * Confirmed Sickle Cell Disease (SCD) (SS, S-b0-thalassemia, S-b+-thalassemia or SC on hemoglobin electrophoresis). * Symptomatic SCD while on 6 months of HU OR symptomatic SCD and intolerant of HU (unable or unwilling to take HU due to hematological or other toxicities). Symptomatic SCD is defined as having one of following: * Fetal Hemoglobin (HbF) \<5%, OR * 3 or more pain episodes per year requiring parenteral narcotics, OR * 1 or more acute chest syndrome episodes, OR * Hemoglobin \<9 g/dL and absolute reticulocyte count \<250,000/mm3. * Subject is in his/her steady state and not amidst any acute complication due to SCD (i.e., hospitalization, acute pain, or acute chest syndrome in the past 14 days). * Regular compliance with comprehensive care and previous therapy. Exclusion Criteria: * Inability to give informed consent. * Experienced severe sepsis or septic shock within the previous 12 weeks. * Last HU dose was ingested within the previous 4 weeks. * Currently pregnant or breast-feeding. * Alanine aminotransferase (ALT) greater than or equal to two times (2X) the upper limit of normal or albumin \<2.0 mg/dL or direct (conjugated) bilirubin greater than or equal to 1.5 mg/dl. * Serum creatinine \>2.9 mg/dL and calculated creatinine clearance \<30 mL/min. * Platelet count \>800 x 109/L. * Absolute neutrophil count \<1.5 x 109/L. * Female of active childbearing potential who is unwilling to use at least one of the two following forms of birth control: (i) not having heterosexual sexual contact beginning at the screening visit and continuing until 4 weeks after the last dose of THU-decitabine OR (ii) intrauterine device (IUD). * Sexually active male who is unwilling to use a condom when engaging in any sexual contact with a female with child-bearing potential, beginning at the screening visit and continuing until 4 weeks after taking the last dose of THU-decitabine. This requirement applies also to males who have had a successful vasectomy. * Altered mental status or recurrent seizures requiring anti-seizure medications. * Moribund or any concurrent disease (e.g., hepatic, renal, cardiac, metabolic) of such severity that death within 24 weeks is likely. * Concurrent diagnosis of malignancy including myelodysplastic syndromes (MDS), leukemia, or an abnormal karyotype. * Vitamin-B12, folate, or iron deficient (until corrected). * New York Heart Association (NYHA) class III/IV status. * Eastern Co-operative Oncology Group (ECOG) performance status greater than or equal to 3. * Participant is on chronic transfusion therapy (e.g., for history of Transient Ischemic Attack (TIA) or stroke) and medically contraindicated to discontinue transfusions (unless multiple allo-antibodies prevent the patient from getting transfusions as scheduled). * Known history of illicit drug or alcohol abuse within the past 12 months. * Other experimental or investigational drug therapy in the past 28 days.