A Study of Nicotinamide With Oral Tetrahydrouridine and Decitabine to Treat High Risk Sickle Cell Disease

Eligibility Criteria

• * Age 18 years or older.
• * Written informed consent provided by the subject before study entry.
• * Confirmed sickle cell disease (SCD) as determined by hemoglobin electrophoresis or liquid chromatography.
• * Subject is in his/her steady state and not having any acute complication due to SCD (i.e., hospitalization, acute pain, or acute chest syndrome in the past 14 days).
• * Weight at least 40kg
• * Regular compliance with comprehensive care and previous therapy.
• * Symptomatic SCD is defined as having one of following, despite at least 6 months of hydroxyurea therapy, or refuse to take hydroxyurea for personal reasons: fetal hemoglobin \<0.5 g/dL, 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.
• * 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) ≥ 3 times the upper limit of normal or albumin \<2.0 mg/dL or direct (conjugated) bilirubin ≥ 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 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 and 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 known Myelodysplastic syndrome, leukemia, or an abnormal karyotype.
• * New York Heart Association (NYHA) class III/IV status.
• * Eastern Co-operative Oncology Group (ECOG) performance status ≥3.
• * Participant is on chronic transfusion therapy
• * Known history of illicit drug or alcohol abuse within the past 12 months.
• * Other experimental or investigational drug therapy in the past 28 days.
• * Taking l-glutamine within the last 28 days
• * Being positive for HIV infection