Routine treatments for sickle cell disease (SCD) are currently limited to blood, stem cell, and bone marrow transplants though other treatment and management strategies are available to help manage anemia and painful episodes amongst other complications with even more promising drugs and treatments being developed currently and in the near future.
Sickle cell disease (SCD) is an autosomal recessively inherited disorder caused by a single mutation at codon 6 of the HBB gene from glutamic acid to valine (E6V) due to a single base change A>T (rs334 mutation) resulting in sickle hemoglobin (HbS). This; whilst in normal circumstances does not lead to any major structural or functional changes in hemoglobin within red blood cells, under certain hypoxic conditions can lead to sickling of red blood cells – which can lead to repeated “vaso-occlusive crises” (VOCs) that can lead to ischemia and severe pain within organ and muscle tissue. The repeated sickling and unsickling of red blood cells also leads to a shorter lifespan of sickle red blood cells compared to healthy red blood cells.
As with many genetic disorders, SCD is largely incurable to the persistent production of faulty hemoglobin (HbS) within new red blood cells, and as such treatment options are limited. The only current “cure” for SCD is lifelong blood, stem cell, and bone marrow transplants, though other treatment strategies do exist and new techniques may prove to be very effective in the future. In this article, a select few promising treatment strategies are discussed though several more novel treatments do exist which are not discussed.
Sickle Cell Disease. Image Credit: Ezume Images/Shutterstock.com
Blood, Stem Cell, and Bone Marrow Transplants
At present, the only real treatment strategy for SCD is lifelong repeated blood, hematopoietic stem cell (HSC), and bone marrow transplants, however, due to the risks involved, they are not done often. The most common and best curative treatment for SCD is that of an allogenic HSC transplant which can drive the production of new donor-derived red blood cells and even reverse some tissue/organ damage.
These are especially effective and safer in younger individuals (16 or under) as it is more toxic (e.g., graft rejection) and less safe for older patients. Though if matched sibling donors (MSD) are used then the likelihood of graft rejection is minimized substantially even in older adults. With newer methods (MSD) and medications (e.g., alemtuzumab & sirolimus), the overall efficacy of transplantation is increasing (over 95% cure rate), and the adverse effects associated with this can be minimized even in adults.
Of course, the biggest limitation with the above approach is that of finding MSDs. An alternative is haploidentical family members and matched unrelated donors (MUDs) who are known to be effective in thalassemia and are currently being trialed for SCD, though the risk of rejection remains higher compared to MSD. With newer immunomodulatory drugs, the risk of graft rejection is becoming lower, and newer approaches becoming safer every year. Gene therapy approaches are discussed later, which use similar transplantation approaches but with the patient’s own cells which vastly reduces the risk of rejection.
Sometimes simple blood transfusions are sufficient for a quick and immediate SCD remedy, however, there are specific challenges with the increased risk of iron overload. This is not such an issue if iron-deficient anemia is present, however, in most cases of SCD, this will not be the case.
Hydroxyurea (Hydroxycarbamide)
Hydroxyurea (HU) is an effective medication that can reduce the frequency of painful episodes and clotting in SCD. HU can induce fetal hemoglobin (HbF) production in favor of faulty sickle hemoglobin (HbS) as well as reducing HbS polymerization. Hydroxyurea is also able to reduce the expression of clot-inducing adhesion molecules in red blood cells, as well as leading to a reduction in the number of platelets, reticulocytes, and neutrophils thus reducing the viscosity of blood as well hemolysis. It can also act as an NO donor thus increasing vasodilation.
As a consequence, hydroxyurea is able to reduce the occurrence of painful VOCs as well as the incidence of acute chest syndrome (ACS) in patients – 2 common complications of SCD. Furthermore, as the blood is more stable after hydroxyurea treatment, it also means that there is less of a requirement for blood, cell, and marrow transfusions. As such, the drug remains one of the best disease-modifying drugs for SCD to date alongside transfusions.
Despite its proven efficacy in the majority of SCD patients, many patients are not routinely given hydroxyurea due to the lack of worldwide clinical awareness of the drug. Furthermore, there are concerns regarding some of the potential side effects which may include teratogenesis and unknown effects on fertility and reproduction.
However, it is important to note that these risks are rare, and the benefits outweigh the risks enormously. In some rare cases, patients may not respond to hydroxyurea perhaps due to genetic differences with respect to HbF production and regulation.
SCD Complications
An array of antibiotic and antimalarial medications, as well as folic acid, are given to minimize the risk of developing secondary complications from other conditions in SCD. Unlike sickle-cell trait which is protective from malaria, SCD is not and malaria in patients with SCD may prove to be fatal thus antimalarial medication is important for people with SCD, especially in endemic areas.
People with SCD should not take iron supplements are the cause of anemia in SCD is not due to iron deficiency (as it is with the more common iron-deficiency anemia).
Gene therapy & novel treatment strategies
As gene editing technologies become more advanced and closer to everyday clinical use, these show the most promise in terms of curing genetic diseases fully. Compared to other genetic diseases, SCD tends to be attributed to a single genetic mutation as described earlier, and as such (theoretically) should be easier to correct in the vast majority of patients e.g, through the use of CRISPR/Cas9 gene editing or other genetic approaches.
Furthermore, there are specific SNPs that are attributed to a higher HbA or HbF production (e.g., downregulation of BCL11A by shRNA) that can also be capitalized on with great efficacy clinically. This leads to many promising avenues for gene therapy in SCD. Unlike in traditional bone marrow transplants (discussed earlier), autologous (host cells e.g., CD34+) can be transfected and transplanted reducing the risk of rejection.
For example, a lentiviral vector encoding the human HBB variant βA-T87Q was transplanted into a patient in 2017 (autologous ex vivo gene transfer). After transfection and transplantation, a steady rise in hemoglobin AT87Q production was observed. This patient who was previously transplantation/transfusion-dependent was now able to produce their own HbA without the requirement of any further transfusions after 88 days. This led to long-term stability in HbA: HbS levels even 6-15 months after transfection and no adverse effects were noted.
A monoclonal antibody against p-selectin (intravenously administered) can reduce vaso-occlusive crises. The adhesion of platelets to red blood cells and other cells is important in the pathogenesis of SCD, and the degree of adhesion correlates with disease severity. The antibody inhibits cell-cell adhesion and is able to reduce VOCs by up to 45%, with as many as up to 20% of patients in one study not experiencing any VOCs at all.
Another treatment option is a small molecule that when bound to HbS increases its oxygen affinity. This allows the HbS molecules to carry more oxygen, reduces red blood cell damage, and increases oxygenation to tissues and organs to reduce VOC and ischemia. In one controlled study, it was observed that the molecule was able to reduce the number of irreversible sickled cells by around 70% (strong reduction in hemolysis) with hospital admissions due to VOC complications also reducing by around 60%. Furthermore, the degree of fatigue and chronic pain also reduced substantially.
In summary, treatment strategies for SCD are dependent on the clinical presentation (e.g., frequency of vaso-occlusive crises) and other comorbid conditions and traits. To date, blood, stem cell, and marrow transfusions remain the gold standard of curative treatment in SCD, however, drugs such as hydroxyurea are also incredibly effective. More recently antibody treatments and gene therapy (in addition to several other novel drugs not discussed) may be fantastic treatments and cures for SCD and current research seems promising for the future of SCD.
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Further Reading
CASGEVY gene therapy eliminates vaso-occlusive crises in sickle cell patients