New advances in sickle cell disease

Excruciating pain episodes, recurrent pneumonias, strokes, severe infections, chronic hemolytic anemia, and secondary pulmonary hypertension are common complications of sickle cell disease, a life-threatening inherited defect in blood that causes normally disc-shaped red blood cells to take on a sickle shape. The hardened sickle- shaped cells clog the bloodstream, creating obstructions that result in severe medical complications.

While the development of new approaches to attack the disease and its complications have challenged scientists, results from new studies presented at the 46th Annual Meeting of the American Society of Hematology highlight new advances, offering promise in the battle against sickle cell disease.

"Medical advances have helped researchers to more than double the life expectancy of people with sickle cell in the last two decades, from about 19 years to 43 years of age," said Michael R. DeBaun, M.D., MPH, Associate Professor of Pediatrics and of Biostatistics, Washington University in St. Louis. "Each advance in treatment and gene therapy holds great promise for 70,000 Americans with sickle cell disease and the millions with sickle cell disease worldwide."


Pulmonary Hypertension in Sickle Cell Disease: Cardiopulmonary Evaluation and Response to Chronic Phosphodiesterase 5 Inhibitor Therapy

Nearly one-third of adults with sickle cell disease (SCD) develop pulmonary hypertension (PH), a rare blood vessel disorder of the lungs in which the pressure in the pulmonary artery (the blood vessel that leads from the heart to the lungs) rises above normal levels and may become life threatening. PH is a risk factor for mortality in SCD, with death rates significantly higher in sickle cell patients with the disorder as compared patients without PH. Pulmonary hypertension can cause fatigue, dizziness, and shortness of breath as blood vessels that supply the lungs narrow, forcing the heart to work harder to push blood through.

It is unclear whether pulmonary hypertension is a marker or a direct cause of mortality for the disease. To tackle the question, a team of researchers from the National Institutes of Health and Howard University in Washington, D.C., conducted a study to better understand PH and to determine how to best evaluate if a specific therapy had any impact on treating it. SCD patients with PH were evaluated in comparison to a control group of SCD patients without the disorder. Researchers evaluated each patient's cardiopulmonary function, including hemodynamic (blood circulation) and arterial measures and a functional capacity walk test. To evaluate if a specific therapy would have any impact on these functional measures, another group of 14 patients with SCD and PH were treated for three months with sildenafil (Viagra), a vasodilator that works by opening the blood vessels or arteries and lowering pulmonary blood pressure. There are ongoing clinical studies and research using sildenafil for pulmonary hypertension, both in adults and children.

Researchers performed cardiopulmonary function tests (noninvasive measures) on a group of 15 patients with SCD and PH and a control group. The study demonstrated that pulmonary hypertension, although relatively mild in the study group, is associated with severe impairments in cardiopulmonary function. The group of seven men and eight women had a mean age of 41 years and were followed for an average of 2.4 years. The group was compared with a matched control group of 11 patients with SCD without PH, consisting of four men and eight women with a mean age of 40.2 years and an average of 2.5 years of follow-up.

Researchers also evaluated if a specific therapy for pulmonary hypertension had any impact on systolic pulmonary artery pressure (PAP, the contraction of the heart by which the blood is forced onward and the circulation kept up) and functional capacity. They treated 14 patients with sickle cell disease and pulmonary hypertension with up to 100 mg of sildenafil three times a day for at least three months. The treatment group included three men and 11 women with a mean age of 40 years who were followed for an average of 2.5 years. All patients participated in a six-minute walk test, the standard test for treatments for pulmonary hypertension that measures how far an individual can walk in six minutes.

When compared to the control group, after treatment with sildenafil for at least three months these patients with SCD and PH experienced statistically significant improvements in both exercise capacity as well as hemodynamic improvement. Initially, these patients had lower maximal oxygen consumption, walked a shorter six-minute distance, demonstrated a greater degree of interstitial lung disease, as measured by chest CT, and had more perfusion impairments, as measured by a ventilation perfusion scan. Chronic treatment with sildenafil decreased pulmonary arterial pressure and increased six-minute walk distance. Sildenafil was well tolerated with only two patients stopping the drug due to headaches. Three episodes of transient eyelid edema not requiring discontinuation of drug were observed. Priapism, or persistent, painful erection, was not observed in the three males treated. However, two of the males treated were on exchange blood transfusions and one had erectile dysfunction, and were therefore protected from the development of priapism.

"Our research found that in patients with sickle cell disease, pulmonary hypertension, although relatively mild, is associated with severe impairments in cardiopulmonary function," according to Roberto Machado, M.D., National Heart, Lung, and Blood Institute and Critical Care Medicine Department, Clinical Center, National Institutes of Health and lead investigator of the study. "However, we also learned some good early encouraging news that therapy with sildenafil seems to have a favorable impact on both pulmonary pressures and functional capacity for these patients, and may help lead to a better quality of life, although more research is still needed."


Hematopoietic Cell Transplantation for Sickle Cell Disease: Updated Results of the Multicenter Trial

Currently, the only potentially curative therapy for sickle cell disease is allogeneic hematopoietic (blood forming) cell transplantation. The goal of this treatment is to eliminate the sickle cells and replace them with donor hematopoietic stem cells that produce red blood cells expressing, at best, no sickle hemoglobin or, at worst, quantities similar to the trait condition. For stem cell transplants to succeed, the donated stem cells must engraft or implant within the recipient's bone marrow, where they will grow to provide a new source of essential blood and immune system cells. While there appears to be a considerable benefit to those who survive with stable engraftment of donor cells, there are also significant health risks to those who undergo this treatment. The results of transplantation are best when performed in children with a sibling donor who is HLA-identical.

To assess the risks and benefits of myeloablative HLA-identical sibling bone marrow transplantation (BMT), which does not completely destroy the patient's diseased marrow, researchers at Children's Hospital Research Center in Oakland, California, evaluated the long-term outcomes of 59 patients with symptomatic sickle cell disease (SCD) who participated in a multicenter clinical trial between 1991 and 2000. Currently, 55 patients survive, and of these survivors, 50 remain free of sickle cell disease.

Of the total patients enrolled in the study, four died of complications from graft-versus-host-disease. Five patients had graft rejection accompanied by return of SCD. The median follow-up of the study was 5.2 years. Twenty- four males and 19 females over the age of 14 are currently in the study.

Before entering the study, 30 patients had stroke, 20 patients had recurrent episodes of acute chest syndrome (ACS), 8 patients had recurrent painful episodes, and one had significant central nervous system disease (CNS). In the long-term follow-up study, designed to investigate the toxicity of transplantation and assess its impact on the natural history of SCD, researchers evaluated the current status of patients with regard to CNS, pulmonary function, and gonadal function.

Long-term analysis showed that patients with stable engraftment of donor cells had cessation of clinical complications of SCD after BMT. In addition, most had stabilization or improvement in sub-clinical markers of disease. A limited number of patients who had progression of pulmonary function testing (PFT) abnormalities also had a history of ACS before BMT. In addition, gonadal toxicity was observed commonly in females after BMT.

Patients who entered the study with stroke had no subsequent stroke events after the BMT. Of the 55 surviving patients, 78 percent had PFT at least one year after BMT. The results indicated that 30 patients had stable and eight had improved pulmonary function, while five patients had worsened function. Of the patients older than 14 years of age, 63 percent of males and 74 percent of females had post-BMT gonadal function studies performed. The outcomes indicated that 11 males had normal leutinizing hormone and follicle- stimulating hormone levels, however a normal testosterone level was observed only in four. In contrast, nine of the females had elevated gonadotropin and decreased estradiol levels that mimicked a post-menopausal state. Six females had primary or secondary amenorrhea.

"While our findings confirm that bone marrow transplants remain a well- established and viable therapeutic intervention for children with severe sickle cell disease, the data also underscore the vital need for finding ways to reduce the toxicity of transplants for these already sick patients," said Mark C. Walters, M.D., Hematology/Oncology Department of the Children's Hospital Research Center at Oakland, California and lead author of the study.


Efficacy and Safety of the Gardos Channel Inhibitor, ICA-17043, in Patients with Sickle Cell Anemia

Investigators from the Department of Medicine at the University of North Carolina, Chapel Hill, NC and from multiple other sites across the U.S. have now reported the results from a dose-range-finding, safety and efficacy study for a new drug being developed to treat sickle cell anemia. The drug, ICA- 17043 (bis(4-fluorophenyl)phenyl acetamide), is a member of a new class of drugs called Gardos Channel Inhibitors.

A prominent feature of sickle cell anemia (SCA) is the presence of dehydrated red blood cells (RBCs) in the circulation. Red blood cell dehydration occurs when ions and water flow out of the red cell, causing the cells to shrink and the intracellular hemoglobin concentration to rise, which vastly increases sickling. A red cell membrane-associated pathway referred to as the Gardos channel is one of the principal routes through which potassium is lost from the cell. By blocking this channel, ICA-17043 prevents accelerated potassium efflux, thereby preventing the cellular dehydration and the attendant rise of intracellular hemoglobin concentration that plays an important pathophysiologic role in sickle cell disease.

The primary outcome variable of this multicenter study was to determine whether ICA-17043 could slow the accelerated red cell destruction that is a characteristic feature in patients with sickle cell anemia.

A total of 90 patients with SCA were enrolled in this parallel-group, randomized, double-blind, dose-range-finding study, eighty of whom completed the 12 week study. The patients were randomized into three groups: low dose of ICA-17043 (6 mg/day); high dose of ICA-17043 (10 mg/day); or placebo. Using an intent-to-treat analysis, the researchers found a statistically significant increase from baseline of the total hemoglobin (Hb) when the subjects in the high dose arm (0.68+/- 0.11 g/dL, S.E.) were compared with those in the placebo arm (0.01+/- 0.12 g/dL). Although an increase in Hb was also seen in the subjects in the low dose arm (0.28+/- 0.15 g/dL), this smaller change failed to reach statistical significance.

In addition to the increase in Hb, statistically significant decreases were noted in a variety of markers of red blood cell destruction (e.g., reticulocyte count, lactate dehydrogenase, and indirect bilirubin) when the patients on high dose ICA-17043 were compared to those on placebo. In addition, the number of dense red blood cells in the peripheral circulation also declined in patients receiving the active drug. ICA-17043 was found to be well-tolerated. The most common adverse experiences in the study were diarrhea and nausea. Although relatively infrequent, these symptoms occurred more often in the subjects receiving active treatment than in those on placebo.

"Our findings are very encouraging. We found that the drug was well- tolerated and improved the hemolytic anemia that is a characteristic feature of sickle cell disease. Treatment with ICA-17043 resulted in a significant increase in hemoglobin and decreased the various markers of red blood cell destruction, thus suggesting that the drug leads to an improved red blood cell survival," said Kenneth Ataga, M.D., assistant professor of medicine in the Division of Hematology-Oncology at the University of North Carolina, Chapel Hill, and lead investigator of the study. "Based on these positive and beneficial outcomes, we are now about to initiate a much larger Phase III study. However, unlike the study reported here that examined the effect of ICA-17043 on hemoglobin level, which is a surrogate marker of the disease, the Phase III study has been designed to examine the drug's effect on the frequency of vaso-occlusive events in patients with sickle cell disease. After all, it is these painful events that are responsible for much of the morbidity and disability of this genetic disorder."


Correction of Thalassemia by Homologous Recombination in Embryonic Stem Cells

Scientists from the Biochemistry and Molecular Genetics Department at the University of Alabama at Birmingham reported success in a mouse model to correct the mutant or deleted globin alleles with patient-derived embryonic stem (ES) cells. To correct the thalassemia, the researchers inserted a normal beta globin gene into a cloned thalassemic mouse's ES cells, thus allowing for increased production of beta globin and the production of healthy red blood cells. Using homologous recombination (derived from the same species) in mouse ES cells, the scientists were able to replace or correct the mutant or deleted globin alleles with a wild-type gene. After selection, 40 percent of the ES cell colonies had correctly integrated the genes. The new targeted cells were then injected into tetraploid blastocysts (early embryos having a chromosome number four times the basic number) to produce mice that are derived solely from the corrected ES cells. The new breed of mice was normal and lacked the characterization of anemia seen in the thalassemic breed.

Thalassemia is a group of related genetic blood disorders, which cause variable degrees of anemia. Hemoglobin (the protein in red blood cells that carries oxygen to the body) is composed of equal amounts of alpha and beta globin chains. The two main types of these disorders are alpha and beta thalassemias, with identification based on which of these globin chains is missing or deficient. Thalassemia occurs most frequently in people of Italian, Greek, Middle Eastern, Southern Asian, and African ancestry. The most common form of treatment for the most severe forms of beta thalassemia is red blood cell transfusion, with the average patient receiving transfusions every two to three weeks, or about 52 pints of blood each year.

Transfusions improve quality of life but lead to a build-up of iron, which becomes toxic to the body and may result in early death from organ failure. Alternatively, some patients may undergo bone marrow transplantation with cells from a matched normal donor. This treatment, however, is not available to all patients and entails significant risk.

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