determination of red cell survival in sickle cell disease and other hemoglobinopathies using biotin labeling

Conditions: Sickle Cell Disease; Thalassemia; Hemoglobinopathy

Summary: background: sickle cell disease (scd) is an inherited disorder of the blood. scd causes red blood cells (rbcs) to die early. this can lead to a shortage of healthy cells. scd and other blood disorders can be managed with drugs or cured with a bone marrow transplant. researchers want to know how long rbcs survive in people with scd and other blood disorders before and after treatment compared to those who had a bone marrow transplant. objective: to learn how long rbcs survive in the body in people with scd and other blood disorders compared to those whose disease was cured with a bone marrow transplant. eligibility: people aged 18 years or older with scd or another inherited blood disorder. people whose scd or blood disorder was cured with a bone marrow transplant are also needed. design: participants will be screened. they will have a physical exam with blood and urine tests. participants will have about 7 tablespoons of blood drawn. in the lab, this blood will be mixed with a vitamin called biotin. biotin sticks to the outside of rbcs. this process is called "biotin labeling of rbcs." the next day, the participant s own biotin-labeled rbcs will be returned to their bloodstream. participants will return regularly to have smaller blood samples (about 2 teaspoons) drawn. these samples will be tested to detect the percentage of cells that have biotin labels. these visits may be every 2 weeks, 4 weeks, or some other interval. participants will continue this schedule for up to 20 weeks or until biotin can no longer be detected....

study description: this study will use biotin-labeling of red blood cells (rbcs) to determine the mean potential lifespan (mpl) of rbcs in patients with sickle cell disease (scd) and other hemoglobinopathies (e.g. thalassemia), including in those receiving disease modifying therapies or who have undergone curative hematopoietic stem cell transplantation (hsct: allogeneic or autologous). previous studies have corroborated the mpl of healthy donor rbcs to be approximately 115 days, while rbcs from patients with scd have a more variable but consistently shorter mpl of approximately 32 days. we recently validated these findings and demonstrated the feasibility, safety, and efficacy of determining mpl of biotin-labeled rbcs in patients with scd before and after transplant, persons with sickle cell trait, and healthy donors. allogeneic hsct is a curative treatment for severe scd with stable, mixed donor-recipient chimerism after hsct sufficient to reverse the sickle cell phenotype by virtue of improved donor red cell survival compared to the ineffective erythropoiesis of scd. hsct, both allogeneic and autologous, are also curative for certain hemoglobinopathies, such as transfusion dependent beta thalassemia (tdt), with donor cells able to overcome the ineffective erythropoiesis in tdt as well. we predict that the hematologic variables associated with red cell survival among patients with scd and other hemoglobinopathies vary between individuals and are affected by disease modifying therapy, including curative therapies. the data generated will refine our understanding of the degree of correction necessary to reverse the clinical phenotype of scd and other hemoglobinopathies, including that needed for autologous gene therapy to be curative. objectives: primary objective: to determine and compare red blood cell survival, by virtue of the mean number of days of detectable biotin-labeled rbcs, in participants with scd and/or other hemoglobinopathies before and after initiation of disease modifying therapy, including those who have undergone hsct. secondary objective: to validate the association of red cell survival with known markers of increased survival, specifically absolute reticulocyte count, hemoglobin f or hemoglobin a percentage, and alpha globin mutation status (scd participants only). exploratory objective: to create and pilot a mathematical model incorporating rbc survival and reticulocyte count to determine the necessary amount of normal hemoglobin or hemoglobin f needed to reverse sickle cell complications. information from participants with inherited high hbf will be used. endpoints: primary endpoint: red blood cell survival via measurement of detectable biotin-labeled rbc with time secondary endpoint: relationship of rbc survival to hematologic parameters. exploratory endpoint: amount of normal hemoglobin or hemoglobin f needed to reverse the sickle cell complications.

Eligibility criteria:
* inclusion criteria: in order to be eligible to participate in this study, an individual must meet all of the following criteria: 1. provision of signed and dated informed consent form 2. stated willingness to comply with all study procedures and availability for the duration of the study 3. male or female, aged 18 years or greater with confirmed diagnosis of scd (all genotypes), thalassemia (beta and/or alpha), or other inherited hemoglobinopathy not otherwise specified. 4. be at steady state for their underlying disease (e.g. scd or thalassemia) or post-bone marrow transplantation status, as evidenced by medical history. 5. ability to have blood samples drawn. 6. for female participants of child-bearing potential, agree to use birth control during study participation. female subjects of child-bearing potential must agree to use a medically acceptable method of birth control such as an oral contraceptive, intrauterine device, barrier and spermicide, or contraceptive implant/injection from start of screening through 4 months after infusion. 7. agreement to adhere to lifestyle considerations throughout study duration exclusion criteria: an individual who meets any of the following criteria will be excluded from participation in this study: 1. consumption of biotin supplements or raw eggs within the last 30 days. 2. blood loss within the previous 8 weeks (\>540 ml). 3. treatment with chronic transfusion therapy for their underlying scd and/or thalassemia. a. participants with history of chronic transfusion therapy can be eligible three months following their last transfusion. 4. patients on hemodialysis, due to possibility of early removal of biotinylated rbcs. 5. pregnancy, lactation or absence of adequate contraception for fertile female subjects. 6. pediatric subjects will not participate in this study. 7. known allergic reactions to biotin, due to risk of possible life-threatening allergic reaction. 8. current diagnosis of malignancy (liquid and/or solid).

Keywords: red cell hemoglobinopathy thalassemia sickle cell disease biotin