Hydroxyurea for the Treatment of Patients With Sickle Cell Anemia

Sickle Cell Anemia

Gene Expression Therapy, Gamma Globin Gene, Hemoglobin Switching, Bone Marrow, Sickle Cell Anemia

A total of fifty severely affected patients with homozygous sickle cell disease or other sickling disorders (e.g. B negative or B positive Thalassemia/Sickle) who are greater than 18 years of age will be eligible for treatment. Such patients must be able to tolerate an extensive period without blood transfusion and have relatively well preserved renal and hepatic function (creatinine less than 1.5 mg/dl and normal liver function test with exception of a mild elevation in transaminase). Evidence of severe sickle cell anemia will include recurrent pain crisis, chronic bone oain, evidence of aseptic necrosis with symptoms, and intractable leg ulcer, etc. On admission to the study, each patient will receive a complete history and physical examination. These data and standard laboratory evaluation, including a test for pregnancy if appropriate, will be adequate to ascertain whether any of the criteria for exclusion are present. Each patient must accept responsibility for for using an effective means of contraception. Patients who are found to be HIV positive will be excluded from the study....

Hydroxyurea is a cell-cycle specific agent that blocks DNA synthesis by inhibiting ribonucleotide reductase, the enzyme that converts ribonucleotides to deoxyribonucleotides. Hydroxyurea has been shown to induce the production of HbF, initially in non-human primates, and now in more than fifty patients with sickle cell anemia. The majority of patients with sickle cell disease respond to the drug with a more than two-fold increase in HbF levels; in some patients the percent of HbF exceeds 10 or 15 percent. It is estimated that levels of 20 percent are required to substantially reduce the sickling propensity of red cells and to modulate disease severity. We propose now to treat several patients chronically with hydroxyurea to monitor the durability of the response, to examine for unanticipated long term sided effects and to determine hematological changes occurring longitudinally. Such patients will be candidates for protocols determining the ability of other agents to enhance HbF synthesis, especially in hydroxyurea non-responders. Finally, a series of in vitro studies are planned to attempt to develop predictors of response.

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