ARRA IMPACT REPORT:
Public Health Burden
The hemoglobinopathies—sickle cell disease (SCD) and thalassemia—are the most common genetic diseases globally. It is estimated that more than 300,000 infants with major forms of these diseases are born each year, and most of them die undiagnosed, untreated, or under-treated. Approximately 100,000 Americans have SCD. They experience repeated episodes of illness throughout life, particularly because of painful crises, and account for 70,000 hospitalizations and more than 200,000 emergency-room visits annually.
Basic research seeks ultimately to uncover effective treatments for SCD by developing new drugs and exploring gene therapy. Examples of progress achieved via ARRA-funded basic investigations are listed below:
Inducing the Production of Fetal Hemogloin: The most promising avenue of research for ameliorating the severity of SCD is the discovery of drugs to induce production of fetal hemoglobin (HbF), which normally is made prenatally but diminishes after birth. A group of investigators at Dartmouth College developed a system that screened 13,000 compounds from a chemical “library” and identified four that induce a 4-fold to 8-fold increase in HbF production. Two of them appear to be suitable candidates for clinical applications.1
Identified Gene Associated with Increased Risk for Gallstones: For reasons that are not well understood, some patients with SCD have more severe clinical problems than others. For example, gallstones affect many, but by no means all, individuals with SCD. A group of researchers at Boston University analyzed the genomes of more than 1,100 patients with SCD and found one gene, UGT1A1, to be significantly associated with a higher risk of gallstones. The discovery enables identification of a subgroup of SCD patients who would likely benefit from careful monitoring for the development of gall bladder disease.2
Genomic Analysis to Study Fetal Hemoglobin Synthesis: The Boston University researchers also performed genomic analyses of SCD patients with either high or low fetal hemoglobin (HbF) levels. They identified four markers for DNA sequences that were more prevalent in the group with high levels. The next steps will be to determine the nature of the proteins that result from the transcription of the DNA sequences, which is expected to shed new light on the mechanisms that regulate HbF synthesis.3
Current options for treating SCD are extremely limited. Stem cell transplantation has curative potential, but entails substantial risk and is available to only a small proportion of patients. The development of new therapies is a major priority.
Better treatments are needed for the repeated episodes of severe pain that many patients with SCD experience. One theory is that the episodes are caused by certain immune cells (iNKT cells) in the blood that trigger a harmful chain reaction.
Using ARRA funding, a team of researchers at Harvard University and the Medical College of Wisconsin developed a new treatment (adenosine) that may interfere with some of the initial steps in the chain reaction. The investigators are now collecting early clinical data on stable SCD patients. If no significant side effects become apparent, they will move on to plan a phase III clinical trial.4
Patients with SCD are given red blood cell transfusions to correct low blood counts, prevent or treat complications, or prepare them for surgery. Recipients of repeated transfusions often develop antibodies (sensitization) to donor red cells, which complicates future transfusions. Strategies to increase the number of donors with racial/ethnic backgrounds similar to those of potential recipients and to improve red cell matching in some individuals to delay or prevent red cell sensitization have been investigated in ARRA-funded research projects.
Immunogenic Profiles to Help Reduce Blood Transfusion Adverse Reactions: An ARRA-funded investigator at the New York Blood Center described an immunologic profile that may allow earlier identification of subjects who would be particularly likely to develop antibodies to transfused red blood cells. More precise matching techniques could be used in such patients to reduce the risk of adverse reactions.5
Strategies to Increase Blood Donation Rate among African Americans: Researchers at the University of Rhode Island investigated an approach based on an established model of behavior change to determine if it could increase the blood donation rate among African Americans. The ARRA-funded study developed 10 strategies that may be useful in interventions tailored for that population.6
Contributing NIH Institutes & Centers
- National Heart, Lung, and Blood Institute (NHLBI)