16 Clinical Trials for Various Conditions
A promising approach for the treatment of genetic diseases is called gene therapy. Gene therapy is a relatively new field of medicine in which genetic material (mostly DNA) in the patient is changed to treat his or her own disease. In gene therapy, we introduce new genetic material in order to fix or replace the patient's disease gene, with the goal of curing the disease. The procedure is similar to a bone marrow transplant, in that the patient's malfunctioning blood stem cells are reduced or eliminated using chemotherapy, but it is different because instead of using a different person's (donor) blood stem cells for the transplant, the patient's own blood stem cells are given back after the new genetic material has been introduced into those cells. This approach has the advantage of eliminating any risk of graft versus host disease (GVHD), reducing the risk of graft rejection, and may also allow less chemotherapy to be utilized for the conditioning portion of the transplant procedure. To introduce new genetic material into the patient's own blood stem cells we use a modified version of a virus (called a 'vector') that efficiently inserts the "correcting" genetic material into the cells. The vector is a specialized biological medicine that has been formulated for use in human beings. Fetal hemoglobin (HbF) is a healthy, non-sickling kind of hemoglobin. The investigators have discovered a gene that is very important in controlling the amount of HbF. Decreasing the expression of this gene in sickle cell patients could increase the amount of fetal hemoglobin while simultaneously reducing the amount of sickle hemoglobin in their blood, specifically the amount in red blood cells where sickle hemoglobin causes damage to the cell, and therefore potentially cure or significantly improve the condition. The gene we are targeting for change in this study that controls the level of fetal hemoglobin is called BCL11A. In summary, the advantages of a gene therapy approach include: 1) it can be used even if the patient does not have a matched donor available; 2) it may allow a reduction in the amount of chemotherapy required to prepare the patient for the transplant; and 3) it will avoid certain strong medicines often required to prevent and treat GVHD and rejection. Our lab studies with normal mice, mice that have a form of SCD, and with cells from the bone marrow of SCD patients who have donated bone marrow for research purposes show this approach is very effective in reducing the amount of sickle hemoglobin in red cells. Our pilot trial testing this approach in 10 patients with SCD has shown that the treatment has not caused any unexpected safety problems, and that it increases HbF within the red blood cells. Our goal is to continue to test whether this approach is safe, and whether using gene therapy to change the expression of BCL11A will lead to decreased episodes of vaso-occlusive crisis pain in people with SCD.
The purpose of this study is to determine whether metformin is effective in the treatment for sickle cell anemia (SCA).
Background: - Sickle cell disease (SCD) is a blood disease. The drug hydroxyurea (HU) is approved to prevent pain crises in people with SCD. Researchers want to see how higher doses of HU affect the blood. This will help them learn about the right dosage of HU to give to people with SCD. Objective: - To improve hydroxyurea dosing in people with SCD. Eligibility: - People age 15 or older with homozygous SCD (HbSS). Design: * Participants will be screened with medical history, physical exam, medication review, and blood and urine tests. * Participants will be in the study for about 15 months. * First 3 months: monthly study visits with blood and urine tests. * After 3 months: participants will take HU as a capsule by mouth. If you are already taking HU, your dose will be increased. * Within a month of starting or increasing HU: participants will keep a daily pain diary for 2 weeks. They will have an echocardiogram (ultrasound) of the heart, a 6-minute walk test. They will complete a quality-of-life questionnaire. * Participants will visit every month until they reach their highest tolerated dose of HU. They may need to come as often as every week sometimes to closely monitor their blood counts. Then they will alternate a phone call one month and a visit the next. At the visits, participants will bring their pill bottle, answer questions about side effects, and have blood tests. * Every 2 months, participants will have a medical history, physical exam, and blood tests. * Every 4 months, participants will have blood and urine tests. They will also complete another 2-week pain diary and quality-of-life questionnaire. * About 12 months after starting or increasing HU, participants will have blood tests, an echocardiogram, and a 6-minute walk test.
Sickle Cell Disease (SCD) is a hereditary anemia that causes the red blood cells to change their shape from a round and doughnut-like shape to a half-moon/crescent, or sickled shape. People who have SCD have a different type of hemoglobin (protein that carries oxygen). This different type of hemoglobin makes the red blood cells change into a crescent shape under certain conditions. Sickle-shaped cells are a problem because they often get stuck in the blood vessels blocking the flow of blood and can cause inflammation and injury to important areas of the body. All babies are born with hemoglobin called fetal hemoglobin (HbF). Soon after birth, HbF production slows down and another hemoglobin called adult hemoglobin (HbA) is made. Clinical studies have shown that increasing the amount of HbF in the blood may prevent sickling of the red blood cells. Vorinostat has been used in the treatment of cancers and in other research studies and information from those suggests that it may help treat SCD by increasing the amount of HbF in the blood. The purpose of this research study is to determine the effectiveness and safety of vorinostat when used to treat SCD.
This is a phase II, open-label, prospective study of T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation for children and adults with hematological malignancies
The overall purpose of this study is to obtain a better understanding of the biological response of red blood cells to sulforaphane contained in fresh broccoli sprouts that have been put through a blending process. This study will use commercially available fresh broccoli sprouts certified by Brassica Protection Products LLC (BroccoSprouts®). This product can also be purchased at some local grocery stores in the produce section. It is believed that NRF2, a transcription factor encoded by the NFE2L2 gene, plays a role in the regulation of defense against oxidative stress. The detrimental accelerated breakdown of sickle cell disease (SCD) red blood cells (SS RBC) is partially due to reduced anti-oxidative capacity. Previous analysis of SS RBC microRNAs revealed that a reduced level of NRF2, the master regulator of anti-oxidative stress capacity, contributes to reduced resistance to oxidative stress and increased hemolysis; NRF2 also induces fetal hemoglobin (HbF), which is known to prevent SS RBC sickling. First, erythroid progenitors from normal and SCD subjects will be tested ex-vivo to find out how sulforaphane, a natural NRF2 activator, affects the oxidative stress capacity, HbF expression, and microRNA expression of red cells. Second, a pilot clinical trial will be conducted to determine the safety and physiological effects of 3 weeks of daily consumption of broccoli sprout homogenate in a cohort of Hb SS/SB0 thalassemia adult SCD patients. During this study, subjects RBCs will be assayed for changes in anti-oxidative stress capacity and microRNA composition in mature SCD red blood cells.
Background: People with sickle cell disease (SCD) have problems with their heart, brain, kidneys, liver, and lungs as they age. These problems may improve after transplant. Researchers want to learn how and why this happens. Objective: To study the benefits of treatments that are intended to cure SCD. Eligibility: People aged 18 and older with SCD who are either receiving curative therapy in the next 3 months or don t have any plans to receive a curative therapy in the next 2 years. Design: At their first visit, participants will be screened with their medical history and a physical exam. Participants will then have a baseline visit. This will take about a week to complete and will include: Blood and heart tests MRI of the brain, heart, and lungs. Participants will lie on a bed that will move into the MRI scanner. Special padding may be placed around their head to keep it still. Interactive games. Participants will complete computer games that test memory, attention, problem solving, language, spatial orientation, processing speed, and emotion. Questionnaire rating quality of life Iothalamate test. An IV catheter will be placed into a vein. A contrast agent will be injected through the IV. Blood will then be collected at different time points. Lung function tests and a 6-minute walk test Vibration controlled transient elastography. A probe placed on the abdomen will measure liver scarring. DOS test. A light attached to the finger or toe will measure blood oxygen. Participants will have an end-of-study visit about 2 years after their baseline visit. This will include repeats of the baseline visit tests.
A promising approach for the treatment of genetic diseases is called gene therapy. Gene therapy is a relatively new field of medicine that uses genetic material (mostly DNA) from the patient to treat his or her own disease. In gene therapy, the investigators introduce new genetic material in order to fix or replace the patient's disease gene, with the goal of curing the disease. The procedure is similar to a bone marrow transplant, in that the patient's malfunctioning blood stem cells are reduced or eliminated using chemotherapy, but it is different because instead of using a different person's (donor) blood stem cells for the transplant, the patient's own blood stem cells are given back after the new genetic material has been introduced into those cells. This approach has the advantage of eliminating any risk of GVHD, reducing the risk of graft rejection, and may also allow less chemotherapy to be utilized for the conditioning portion of the transplant procedure. The method used to introduce the gene into the patient's own blood stem cells is to engineer and use a modified version of a virus (called a 'vector') that efficiently inserts the "correcting" genetic material into the cells. The vector is a specialized biological medicine that has been formulated for use in human beings. The investigators have recently discovered a gene that is very important in the control of fetal hemoglobin expression. Increasing the expression of this gene in sickle cell patients could increase the amount of fetal hemoglobin while simultaneously reducing the amount of sickle hemoglobin in their blood, and therefore potentially cure the condition. In summary, the advantages of a gene therapy approach include: 1) it can be used even if the patient does not have a matched donor available; 2) it may allow a reduction in the amount of chemotherapy required to prepare the patient for the transplant; and 3) it will avoid the strong medicines often required to prevent and treat GVHD and rejection. The goal is to test whether this approach is safe, and whether using gene therapy to change the expression of this particular gene will lead to increased fetal hemoglobin production in people with sickle cell disease.
Multi-phase, patient navigator-based program in the Richmond and Tidewater regions of Virginia to demonstrate: 1. the feasibility of using patient navigators to improve the percentage of children and adult (age 15 and older) patients with sickle cell disease (SCD) in SCD specialty care 2. the efficacy of using patient navigators to improve hydroxyurea (HU) (re-)initiation and adherence among adult patients with SCD eligible for HU (Patient navigators may also be known as public health workers.)
The purpose of the study is to determine the maximum tolerated dose, safety and effect on induction of fetal hemoglobin of pomalidomide in patients with Sickle Cell Disease.
The goal of this clinical research study is to find out about the safety and effects of a drug called panobinostat when given to adults with sickle cell disease. Panobinostat is a pan histone deacetylase (HDAC) inhibitor. HDAC inhibitors have been shown to significantly increase hemoglobin F induction, which is well documented to improve outcomes in sickle cell disease. HDAC inhibitors are also known to potently inhibit cell-specific inflammation, which is a primary contributor to the debilitating effects of sickle cell disease. Given the relevance of these mechanisms of action in SCD, panobinostat may prove to contribute significantly to the management of SCD patients, a population in critical need of further effective treatment options.
This study will examine the use of hydroxyurea and erythropoietin for treating sickle cell disease in patients who also have kidney disease or pulmonary hypertension (high blood pressure in the lungs). Hydroxyurea increases production of fetal hemoglobin in the red blood cells of patients with sickle cell disease, reducing the amount of sickle cells that cause pain and other complications requiring hospitalizations. However, hydroxyurea treatment has limitations: patients with sickle cell disease who have developed kidney disease may not be able to get the full benefit of the medicine, and hydroxyurea alone may not be able to treat life-threatening complications such as pulmonary hypertension or stroke. This study will determine which of two dosing schedules of hydroxyurea and erythropoietin is more effective for treating patients with sickle cell disease who also have kidney disease or pulmonary hypertension, and will examine whether the two drugs can lower blood pressure in the lungs. Patients 18 years of age and older with sickle cell anemia and kidney disease or pulmonary hypertension, or both, may be eligible for this study. Candidates are screened with a medical history, physical examination, blood tests, a 6-minute walk test (test to see how far the subject can walk in 6 minutes), and echocardiogram (ultrasound of the heart to measure blood pressure in the lungs). Participants undergo the following tests and procedures: Stabilization Phase: Patients take 2 hydroxyurea tablets a day until their fetal hemoglobin levels stabilize, usually over 2 to 4 months. They have blood tests every 2 weeks to monitor hemoglobin and fetal hemoglobin levels. At some time during this period, they undergo a test to measure kidney function, in which they are injected with an iodine-containing dye and wear a small pump for 1 day that injects a small amount of dye under the skin over 24 hours. They come to the clinic for 2 or 3 blood tests collected over 4 hours. Sequence I (Standard): When the fetal hemoglobin levels have been stable for 2 months, patients have a repeat echocardiogram and 6-minute walk test. Erythropoietin is then added to the hydroxyurea regimen. It is given 3 days a week, as an injection under the skin, along with iron supplements. Patients have blood tests and blood pressure measurements every week or every other week. Patients with pulmonary hypertension have another echocardiogram and 6-minute walk test once the hemoglobin level is stable. Sequence II (Cycled): When hemoglobin levels have stabilized with hydroxyurea once a day and erythropoietin 3 times a week, the hydroxyurea is adjusted so that the amount taken in 7 days is "cycled" over 4 days, and the erythropoietin is cycled over 3 days, with the dose increased twice, every 3 to 4 weeks. Blood pressure and hemoglobin are monitored once or twice a month. Patients with pulmonary hypertension have another echocardiogram and 6-minute walk test once the hemoglobin level is stable. Patients who develop complications while taking the drugs have their treatment regimens adjusted as needed.
Patients with sickle cell disease have abnormal hemoglobin (the protein in red blood cells that carries oxygen to the body). This abnormality causes red blood cells to take on a sickle shape, producing disease symptoms. Fetal hemoglobin, a type of hemoglobin present in fetuses and babies, can prevent red cells from sickling. The drug hydroxyurea increases fetal hemoglobin production in patients with sickle cell disease by making a molecule called nitric oxide. The drugs L-arginine and Sildenafil (Viagra) increase the amount or the effect of nitric oxide. This study will evaluate: * The safety of giving L-arginine or Sildenafil together with hydroxyurea in patients with sickle cell disease; * The effectiveness of L-arginine plus hydroxyurea or Sildenafil plus hydroxyurea in increasing fetal hemoglobin in patients with sickle cell disease; and * The effectiveness of L-arginine plus hydroxyurea or Sildenafil and hydroxyurea in lowering blood pressure in the lungs of patients with sickle cell disease. (Pulmonary blood pressure is elevated in about one-third of patients with sickle cell disease, and this condition increases the risk of dying from the disease.) Patients with hemoglobin S-only, S-beta-thalassemia, or other sickle cell disease genotype may be eligible for this study. Before starting treatment, patients will have a complete medical history and physical examination. All patients will take hydroxyurea once a day every day by mouth for at least 2 months. They will be admitted to the NIH Clinical Center to take their first dose of hydroxyurea, and will have blood drawn through a catheter (plastic tube placed in a vein) every hour for 6 hours for tests to determine nitric oxide levels. After discharge, they will return to the clinic once every 2 weeks to check for treatment side effects and for blood tests to monitor hemoglobin and fetal hemoglobin levels. After fetal hemoglobin levels have been stable for 2 months, patients will be admitted to the Clinical Center for their first dose of L-arginine (for men) or Sildenafil (for women). Again, blood samples will be collected through a catheter once an hour for 6 hours. If there are no complications, patients will be discharged and will continue taking hydroxyurea once a day and L-arginine or Sildenafil three times a day for at least 3 months until fetal hemoglobin levels have been stable for at least 2 months. Patients will return to the clinic for blood tests every week for 2 weeks and then every 2 weeks to monitor hemoglobin and fetal hemoglobin levels and to check for treatment side effects. Patients will have eye examinations before and during treatment. Some patients with sickle cell disease develop abnormalities in the blood vessels of the eye. Also, Sildenafil can cause temporary changes in color vision. Rarely, more serious eye problems can occur, such as bleeding from the eye blood vessels or damage to the retina a layer of tissue that lines the back of the eye. Patients will also have an echocardiogram (ultrasound of the heart) before beginning treatment, after hydroxyurea treatment, and after 1 and 3 months of combined treatment with hydroxyurea and L-arginine or Sildenafil to help measure blood pressure in the lungs. Patients who develop complications from L-arginine or Sildenafil may continue in the study on hydroxyurea alone. Patients whose fetal hemoglobin levels increase with the combination therapy of hydroxyurea and L-arginine or Sildenafil may continue to take them.
This study will evaluate the safety and effectiveness of 5-azacytidine and phenylbutyrate for treating thalassemia major. Patients with this disease have abnormal production of hemoglobin (the oxygen-carrying protein in red blood cells), which leads to red blood cell destruction. As a result, patients require frequent red cell transfusions over many years. Because of these transfusions, however, excess iron is deposited in various body organs-such as the heart, liver, thyroid gland and, in men, the testes-impairing their function. Fetal hemoglobin-a type of hemoglobin that is produced during fetal and infant life-can substitute for adult hemoglobin and increase the levels of red cells in the body. After infancy, however, this type of hemoglobin is no longer produced in large quantities. 5-azacytidine can increase fetal hemoglobin levels, but this drug can damage DNA, which in turn can increase the risk of cancer. This study will try to lessen the harmful effects of 5-azacytidine by using only one or two doses of it, followed by long-term therapy with phenylbutyrate, a drug that may be as effective as 5-azacytidine with less harmful side effects. Patients 18 years of age and older with severe thalassemia major may be eligible for this study. Before beginning treatment, candidates will have a medical history and physical examination, blood tests, chest X-ray, electrocardiogram (EKG), bone marrow biopsy (removal of a small sample of bone marrow from the hip for microscopic examination) and whole-body magnetic resonance imaging (MRI). For the biopsy, the area of the hip is anesthetized and a special needle is inserted to draw bone marrow from the hipbone. For the MRI scan, a strong magnetic field is used to produce images that will identify sites where the body is making red blood cells. During this procedure, the patient lies on a table in a narrow cylinder containing a magnetic field. Earplugs are placed in the ears to muffle the loud thumping sounds the machine makes when the magnetic fields are being switched. An intravenous (IV) catheter (flexible tube inserted into a vein) is placed in a large vein of the patient's neck, chest or arm for infusion of 5-azacytidine at a constant rate over 4 days. Patients who do not respond to this first dose of 5-azacytidine will be given the drug again after about 50 days. If they do not respond to the second dose, alternate treatments will have to be considered. Patients who respond to 5-azacytidine will begin taking phenylbutyrate on the 14th day after 5-azacytidine was started. They will take about 10 large pills 3 times a day, continuing for as long as the treatment is beneficial. All patients will be hospitalized for at least 6 days starting with the beginning of 5-azacytidine therapy. Those who are well enough may then be discharged and continue treatment as an outpatient. Patients will be monitored with blood tests daily for 2 weeks and then will be seen weekly for about another 5 weeks. Bone marrow biopsies will be repeated 6 days after treatment begins and again at 2 weeks and 7 weeks. MRI will be repeated 7 weeks after treatment begins. After 7 weeks, patients will be seen at 3-month intervals. Bone marrow biopsies will be done every 6 months for the first 3 years after treatment. Patients will have red cell transfusions as needed and chelation therapy to remove excess iron.
Sickle cell anemia is a genetic disorder that results from a single nucleotide substitution in codon 6 of the beta-globin gene which, in the homozygous state, produces an abnormal hemoglobin that is prone to polymer formation when deoxygenated. The polymerized hemoglobin leads to impaired deformability and sickling of red blood cells which subsequently lodge in end-arterioles producing the classic and most prominent feature of the disorder, repeated vasoocclusive crises. Despite knowledge of the precise genetic defect for decades, only recently has there been therapeutic impact based upon this knowledge when a clear benefit from treatment with hydroxyurea, a cell cycle-specific agent administered to induce production of fetal hemoglobin (HbF) by stimulating gamma-globin synthesis, was reported in patients with sickle cell disease (SCD). The reduction in the frequency and severity of vasoocclusive crises seen has been attributed to the increase in HbF levels in responsive patients. While the majority of patients demonstrate a rise in HbF, not all such patients benefit from treatment. Given these results, alternative agents that also stimulate the production of HbF warrant investigation in the treatment of SCD. Recombinant-methionyl human stem cell factor (SCF) is a hematopoietic growth factor with activity on immature hematopoietic progenitor cells. SCF stimulates the production of HbF in vitro and in vivo, and this effect is attainable without the myelosuppression associated with hydroxyurea. In this phase I/II trial, we will administer SCF in a dose escalating fashion to patients with sickling disorders. Parameters to be measured are HbF levels, F cell levels, peripheral blood CD34 levels, frequency, duration, and severity of vasoocclusive crises, and toxicity.
The investigators aims to evaluate the safety of in utero hematopoietic stem cell transplantation in fetuses with alpha-thalassemia major performed at the time of in utero transfusion of red blood cells.