Gene Therapy:
A Hope for Sickle Cell Disease
by: Rea Shane Yonzon
Healthy red blood cells (RBCs) are round and flow via small blood vessels to transport oxygen throughout the body. In some people, these RBCs resemble a C-shaped farm tool known as a "sickle." These RBCs are hard and sticky, and they get stuck and obstruct the blood flow when they pass through small blood vessels. This condition is known as sickle cell disease (SCD). SCD is a genetic disorder caused by a mutation in the HBB gene, which codes for a critical protein in hemoglobin. Hemoglobin typically allows RBCs to be disc-shaped, but a mutation in the HBB gene causes them to stack together, altering the structure of the RBCs and giving them the distinctive "sickle" shape. SCD is passed down when a child inherits two sickle cell genes, one from each parent. It is distinguished by a low RBC count (anemia), recurring infections, and periods of pain.
SCD affects roughly 100,000 people in the United States
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It affects roughly 1 in every 365 Black or African-American births and about 1 in every 16,300 Hispanic-American births. Furthermore, approximately 1 in every 13 Black or African-American babies is born with the sickle cell trait
With that said, a novel reproductive genetic technology will be made available in the near future.
SCD can only be cured through a bone marrow or stem cell transplant. Bone marrow is a soft, fatty tissue found at the middle of the bones that produces blood cells. A bone marrow or stem cell transplant is a treatment in which healthy blood cells from one person—the donor—are transplanted into someone whose bone marrow is not functioning properly.
Bone marrow or stem cell transplants are extremely dangerous and can result in major side effects, including death. It also comes with a lot of potential adverse effects, such as graft-versus-host disease and an increased risk of infection due to immunosuppressive medicines. The bone marrow must also be a close match for the transplant to work. A brother or sister is usually the ideal donor. And only about 20% of individuals with SCD have a matching sibling. Bone marrow or stem cell transplants are reserved for children with severe SCD who have limited organ damage from the condition.
There are also various drugs available to treat SCD. One of the most well-known is hydroxyurea. It raises fetal hemoglobin levels. This medication, however, must be taken on a daily basis, and not everyone has access to specialized hematology care. It also has negative effects on some people, so it does not work for everyone.
To address such valid concerns, researchers have attempted to use gene therapy to tackle
SCD.
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They tested an approach that stimulate the body's production of fetal hemoglobin. A virus delivers DNA for the production of a small string of genetic material known as a microRNA into cells from a patient's bone marrow. The virus, known as a vector,
permanently inserts the DNA into the genetic material of the cell. The microRNA then interferes with the synthesis of a protein that hinders the formation of fetal hemoglobin. When the protein is inhibited, fetal hemoglobin production resumes. A steady stream of healthy hemoglobin can flow into the bloodstream, compensating for the defective form, just like turning on a faucet.
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In the clinical trial of this gene therapy, patients must have their cells harvested by IV. This requires a three-day hospital stay and may need to be repeated several times. The cells are then brought to the laboratory, where the vector inserts the DNA into a sufficient number of cells. Patients are subsequently admitted to the hospital for around a month to get chemotherapy. Chemotherapy is required because the bone marrow cells that have not been collected must be practically wiped out in order for the cells that are being given back, also via IV, to set up shop and produce.
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Because it is your own cells, there is no issue with immunosuppression in gene therapy.
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Graft rejection and graft-versus-host disease are also not risks of gene therapy. The only challenge present in gene therapy is associated with chemotherapy. Chemotherapy has numerous side effects and risks, including acute short-term risks such as hearing loss and nausea. It also carries certain long-term risks, such as infertility and an increased risk of blood malignancies.
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For the longest time, there were no novel SCD therapy. These technologies took a long time to develop since they are dependent on ongoing basic science research. But, more importantly, the SCD patient population has historically been ignored and lacks a lot of power. If this disease had afflicted other sectors of the population, therapy development could have been faster.
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On the brighter side, given the rate at which newer treatments, including gene therapies, are being developed, there is a good chance that one or more of these therapies will be effective and safe. In theory, these treatments will be available to everyone who does not have a bone marrow match. And that is already a significant difference from traditional bone marrow transplants.​
REFERENCES:
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[1] Living With Sickle Cell Disease. (2021, March 4). Verywell Health. https://www.verywellhealth.com/sickle-cell-anemia-2861015
[2] NIH researchers create new viral vector for improved gene therapy in. (2019, October 2). National Institutes of Health (NIH). https://www.nih.gov/news-events/news-releases/nih-researchers-create-new-viral-vector-improved-gene-therapy-sickle-cell-disease
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