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Advancing Treatments and Cures for Sickle Cell Disease

The NHLBI launched the Cure Sickle Cell Initiative in 2018 to support the development of gene-based cures for sickle cell disease (SCD) that will work for all patients, including those ineligible for bone marrow transplants. Researchers involved in the Cure Sickle Cell Initiative helped develop an accurate, affordable, and easy-to-use device for point-of-care diagnosis of SCD in low-resource areas. Read our feature on how this test may transform SCD screening and safe lives around the world.

In early 2020, the NHLBI also became an integral part of a collaboration between NIH and the Bill & Melinda Gates Foundation to develop affordable, safe, and effective gene-based cures for SCD in sub-Saharan Africa. The Cure Sickle Cell Initiative also includes an analysis to ensure that new therapies will be beneficial to patients in ways that matter to them, including affordability and accessibility.

Also in 2020, NHLBI-supported researchers discovered that SCD causes abnormal twists and turns in the blood vessels that supply bone marrow, where red blood cells are made. These disorganized blood vessels deprive the bone marrow of oxygen and could complicate efforts to restore normal red blood cells to patients, such as through bone marrow transplantation or gene therapy. However, in studies on mice, these researchers found that six weeks of blood transfusion restored normal blood vessel architecture in the bone marrow, suggesting a similar protocol could be used as part of cell- and gene-based therapies in patients.  

In late 2020, NHLBI-funded researchers reported promising results in a pilot trial of gene therapy to restore the body’s hemoglobin, the red blood cell protein altered in people with SCD. At birth, the body normally switches from making fetal hemoglobin (HbF) to making only adult hemoglobin (HbA). The trial is testing a gene therapy to turn off the switch—a molecule called BCL11A—turning on HbF to replace HbA. Over a median of 18 months, six participants with severe SCD who received this therapy had robust HbF induction, fewer crises and other disease-related events, and less need for transfusions.

Healthcare barriers continue to be an issue for people with SCD. The NHLBI’s Sickle Cell Disease Implementation Consortium surveyed 440 adolescents and adults with SCD and found that most were pleased with their primary care but had negative experiences with emergency care during a sickle cell crisis. To address this challenge, one study is embedding each patient’s individualized pain treatment plan in their electronic health records so that it can be accessed quickly by emergency care providers. In another study, researchers are collaborating with patients to develop and test a smartphone app that helps patients who are prescribed hydroxyurea remember to take it regularly. Hydroxyurea can help reduce the frequency of sickle cell crises.

Map showing the NHLBI Sickle Cell Disease Implementation Consortium study sites
Map showing the NHLBI Sickle Cell Disease Implementation Consortium study sites in Augusta, GA; Charleston, SC; Chicago, IL; Durham, NC; Memphis, TN; New York, NY; Oakland, CA; St. Louis, MO. Coordinating center in Rockville, MD.

Improving Blood Storage and Transfusion Medicine

Refrigerated storage of red blood cells (RBCs) leads to a series of biochemical changes, referred to as storage lesion, that eventually causes damage to the RBCs and a breakdown of their antioxidant systems. Ongoing NHLBI-funded studies aim to better understand the aging of stored RBCs to evaluate how to reduce storage lesion or potentially mitigate its effects. One NHLBI-funded team has developed a cocktail of four chemicals— phosphate/inosine/pyruvate/adenine (PIPA)—to “rejuvenate” stored RBCs by giving them a boost of antioxidants.  After showing that PIPA can improve the function of RBCs in the lab, the researchers compared blood transfusion using RBCs treated with PIPA versus use of standard RBC products in patients with SCD.  They found that after transfusion, blood from patients with SCD who received the rejuvenated RBCs had markers for higher antioxidant and energy metabolism than blood from patients who received standard exchange transfusions.

The Recipient Epidemiology and Donor Evaluation Study (REDS) is also examining aspects of blood processing that could affect RBC metabolic changes during storage. For example, recent findings show that additives used in the RBC storage bag can affect RBC metabolism.

In addition, the RBC-Omics study, which was developed under the REDS program, is looking at blood samples from 13,400 healthy individuals to examine donor characteristics, such as genetics and diet, that are associated with metabolic aging and breakdown of stored RBCs. RBC-Omics will shed light on how genetic or biological variations in donors, including iron levels, affect the metabolic age of stored RBCs, as well as transfusion outcomes in recipients. Other REDS studies recently found that iron supplements can help correct iron deficiencies in people who donate whole blood frequently and that a donor’s health-related habits (such as smoking, or drinking caffeine or alcohol) can affect the quality of stored donated blood and transfusions.

Examining the Blood-Brain Barrier

The blood-brain barrier (BBB) is made up of tightly joined cells that protect the brain from pathogens and toxins in the blood. But it can also prevent brain access to potentially helpful drugs, such as those under study for dementia and brain injuries. A new program, jointly funded by the NHLBI and the Department of Defense Joint Program Committee-6, Combat Casualty Care Research Program, is investigating the crosstalk between the BBB and the blood — the first time this has been attempted on a large scale. The program aims to build tiny bioengineered BBB models that can help reveal mechanisms of neurological disease and injury, characterize the role of individual blood components, and potentially identify new therapies and diagnostic tools.

Eight circles with four colored circles in the middle
Meeting NHLBI Strategic Vision Objectives 1, 2, 4
An illustration of blood flowing through the blood-brain barrier landscape. Courtesy of Edward Neuwelt, M.D., Oregon Health & Science University.
An illustration of blood flowing through the blood-brain barrier landscape. Courtesy of Edward Neuwelt, M.D., Oregon Health & Science University.