Sickle cell anemia is an inherited disorder that affects the red blood cells, or the cells that transport oxygen throughout the body. The disease is characterized by abnormal, sickle-shaped red blood cells, which may become trapped inside blood vessels. This may lead to inflammation, chronic pain and insufficient oxygen being transported to tissues and organs.
Stem cell transplants may reverse some cases of sickle cell anemia, but this is risky option and not possible for everyone. Research is ongoing to identify more effective ways of treating sickle cell anemia as well as a more robust potential cure.
Sickle cell anemia is caused by a mutation in the HBB gene. This gene provides the instructions to produce hemoglobin, the protein inside red blood cells that carries oxygen. The mutated hemoglobin in sickle cell anemia sticks together or polymerizes, forming a rigid structure inside the cells. This results in deformed red blood cells with reduced flexibility that cannot easily pass through tight blood vessels.
Gene therapy aims to introduce a normal, functioning copy of the HBB gene inside the patient’s cells so they can produce normal hemoglobin. This should reduce the numbers of sickle-shaped red blood cells that cause problems, and ultimately reduce or prevent the symptoms of the disorder.
Several methods of gene therapy are currently in clinical trials for sickle cell anemia. Many of these methods involve harvesting hematopoietic stem cells from the patient. Hematopoietic stem cells are the source of new blood cells. These can then be genetically modified in the laboratory to produce the normal healthy hemoglobin protein, then transplanted back into the patient. Once these cells have established themselves in the patient, they should be a source of healthy red blood cells.
CTX001, by CRISPR Therapeutics, is another type of gene therapy that aims to modify hematopoietic stem cells to produce a form of hemoglobin known as fetal hemoglobin, which is normally only produced in a fetus.
Voxelotor (previously GBT440) is an experimental therapy, by Global Blood Therapeutics, that aims to prevent the abnormal hemoglobin from polymerizing inside cells. It is hoped that by preventing this, even with the abnormal hemoglobin, the red blood cells will be able to maintain a somewhat normal shape and function. Voxelotor is currently being investigated in Phase 2 (NCT02850406) and Phase 3 (NCT03036813) clinical trials.
There are several medications being investigated to treat the symptoms of sickle cell anemia, especially the debilitating pain patients experience.
NKT Therapeutics is developing NNKTT120, an investigational treatment to reduce levels of a type of immune cell that causes inflammation. Results of a Phase 1 clinical trial (NCT01783691) have been published in the scientific journal PLoS One and showed that NNKTT120 successfully depleted inflammatory cells in adults with sickle cell anemia.
Improving blood flow
In sickle cell anemia, blood flow can be restricted by the abnormal red blood cells blocking blood vessels, but also by the walls of the blood vessels narrowing in response to inflammation and damage.
Various therapies are aimed at improving blood flow, which should help reduce the symptoms of sickle cell anemia. IW-1701 is being developed by Ironwood Pharmaceuticals to increase levels of nitric oxide, a substance involved with relaxing the walls of the blood vessels. A Phase 2 clinical trial (NCT03285178) is testing the effect of IW-1701 in patients.
Bayer’s riociguat is approved to relax blood vessels in pulmonary arterial hypertension, a disease associated with restricted blood flow in the blood vessels of the lungs. Researchers at the University of Pittsburgh are investigating whether riociguat can also help improve blood flow in sickle cell anemia, in a Phase 2 clinical trial (NCT02633397).
Ticagrelor is a blood-thinning medication produced by AstraZeneca that is being investigated to see whether it can help keep blood cells from forming clumps and blocking blood vessels. A planned Phase 3 trial (NCT03615924) will be recruiting children with sickle cell anemia worldwide.
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