How Does Sickle Cell Disease Occur – Sickle cell anemia (SCA) was first described in Western literature more than 100 years ago. The elucidation of its molecular basis has stimulated many biochemical and genetic studies and contributed to a better understanding of its pathogenesis. Unfortunately, the translation of such knowledge into treatment development has been slow and elusive. In the last 10 years, the discovery of a major γ-globin gene suppressor, BCL11A, has led to a better understanding of the fetal-to-adult hemoglobin transition and a resurgence of exploration of pharmacological and gene/genetic approaches to fetal hemoglobin regeneration. Possible treatments. Along with therapeutic reprogramming of fetal hemoglobin, stem cell transplantation and hybrid hermerism as well as gene editing and gene editing have yielded encouraging results. Other advances have contributed to the FDA’s approval of three new drugs for the management of sickle cell disease in 2017 and 2019, and several others are currently in development. In this review, we will focus on the most important advances of the last decade.
Sickle cell disease (SCD) is an inherited blood disorder that first appeared in Western literature in 1910. When he examined his blood fluid, he discovered many abnormally shaped red blood cells and began to hypothesize that “… the cause of the disease may be an unrecognized change in the red blood cells themselves” (Herrick, 2014). More than 100 years later we recognized that the red corpuscle mutation was caused by a single base substitution in β-globin, and that the disease was widespread in areas with a history of malaria, not just in the United States (USA). Locality includes sub-Saharan Africa, India, the Middle East, and the Mediterranean (Williams and Thein, 2018). The presence of SCD in non-malarial areas is associated with recent migration patterns.
How Does Sickle Cell Disease Occur
About 300,000 infected babies are now born each year, more than 80% of them in Africa. Due to recent population migration, there is an increase in individuals affected by SCD in non-malarial countries such as the United States. An estimated 100,000 Americans are affected by SCD, the majority of whom are of African descent (Hassell, 2010, 2016). The number of people affected by SCD is expected to increase dramatically Piel et al. (2013) Between 2010 and 2050, the total number of births affected by SCD will be 14,242,000 Human migration and globalization will continue to spread SCD worldwide in the coming decades. Although more than 75% of newborns with SCD in sub-Saharan Africa do not survive their fifth birthday (McGann, 2014), almost all affected infants in middle- and well-to-do countries can expect to survive into adulthood, but overall survival remains in the 20s. 30 years behind those without SCD (Telfer et al., 2007; Quinn et al., 2010; Elmariah et al., 2006). Until the World Health Organization recognized SCD as a global public health problem.
Caring For Your Child With Sickle Cell Disease
In 1949, Linus Pauling demonstrated that an abnormal protein (hemoglobin S, HbS) causes anemia in sickle cells, making SCD the first molecular disease and triggering tremendous scientific and medical research. Because of its genetic simplicity, SCA has been used to describe many advances in molecular genetics, such as detection of DNA mutations by restriction fragment enzyme analysis, and as a proof-of-principle for our current polymerase chain reaction (PCR). taken for granted (Wilson et al., 1982; Saiki et al., 1985).
Over the past 50 years, tremendous progress has been made in understanding the pathogenesis and pathophysiological complexity of SCD, but development of treatments has been incomparably slow and elusive. The history of peril and progress is thus summarized directly by Vailo (2017). We believe that over the next 30 years, the treatment landscape for SCD will change due to a combination of recent advances in genetics and genomics, the proliferation of competitive clinical trials, and increased awareness from funding agencies. Especially NIH, USA.
Here, after a brief review of the pathophysiology, we focus on advances in the treatment of SCD that have occurred in the last 10 years and have reached phase 2/3 clinical trials (Figure 1).
Figure 1. Timeline of historical events since the diagnosis of sickle cell disease in the last decade. SCD, sickle cell disease HSCT, ischemic stem cell transplantation HU, hydroxyurea.
Sickle Cell Disease
) in which the glutamic acid at position 6 of the β-globin chain of hemoglobin is changed to valine. Goldstein et al. . Genetic causes of SCD include mutations in rs334 (HbSS, also commonly known as SCA) and compound heterozygosity between rs334 and the mutation. – Globin production is similar to that in β-thalassemia (HbS/β-thalassemia). In patients of African ancestry, HbSS is the most common SCD (65%–70%), followed by HbSC (approximately 30%), and HbS/β thalassemia is responsible for most of the rest (Steinberg et al.). The intracellular concentration of HCA is nearly 100% that of SCA, the most severe and well described to date (Brittenham et al., 1985). Much of the development of treatments and interventions has focused on this type of gene, although other SCD genes have been affected.
A fundamental event underlying the complex pathogenesis and multisystem consequences of SCD is the polymerization of HbS that occurs under low oxygen tension (Figure 2). Polyionization of oxygenated HbS alters red blood cell (RBC) structure and function. These damaged (usually coiled) RBCs are not only more flexible than normal RBCs, but also more viscous. Repeated coiling and sickle cell cycles reduce the lifespan of damaged coiled RBCs to approximately 6/6 of that of normal RBCs (Bunn, 1997; Hebbel, 2011). The resulting vascular occlusion and chronic hemolytic anemia in almost all organs of the body, two hallmarks of the disease, lead to recurrent acute clinical events, of which acute pain is the most common, and cumulative organ damage. Acute colic pain is so severe that it is often called a “vascular crisis” or VOC.
Figure 2 Hb S, hemoglobin S.
These events trigger a variety of pathogenic factors, including neurons, platelets, and vascular endothelium, to induce proinflammatory activity in the disease (Sundd et al., 2019). Continuous release of cell-free hemoglobin from hemolysis consumes hemopexin and haptoglobin, resulting in decreased nitric oxide (NO) bioavailability and vascular endothelial dysfunction underlying chronic organ damage in SCD pathology.
Sickle Cell Disease (chapter 17)
Erythrocytes not only interact with the vascular endothelium, but also promote the activation of neutrophils, monocytes, and platelets. At baseline, SCD patients have normal values of neutrophils, monocytes, and platelets that are increased during acute episodes (Villagra et al., 2007). Neutrophilia has been consistently associated with SCD severity (Ohene-Frempong et al., 1998; Miller et al., 2000); Neutrophils play a major role by interacting with both erythrocytes and endothelium, P- and E-receptors, and are current therapeutic targets (Jang et al.).
When platelets are activated, they aggregate with erythrocytes, monocytes, and neutrophils in patients and muscle models (Wun et al., 1997; Zhang et al., 1997). Like neutrophils, platelet aggregation depends on P-selin. As part of this chronic inflammation, coagulation cascades are also overactivated in SCD. Repeated interaction of RBCs with endothelium induces the expression of adhesive and epithelial proteins. Patients with SCD have increased rates of venous and arterial thrombotic events (Brunson et al., 2017).
Unraveling these pathophysiological targets has informed clinical trials of anti-platelet and anti-adhesion drugs, as well as anti-coagulant factors in the prevention of acute VOC pain in SCD (Thelen, 2016; Nasimzuzaman and Malik, 2019; Thelen et al. ., 2019). One example is the development of an anti-P selection molecule (Crizanlizumab) for the treatment of coiled VOCs, recently approved by the FDA in November 2019 and marketed as Adakveo.
New therapeutic approaches that use drugs to ameliorate downstream complications of HbS polymerization have not been shown to be as effective as “anti-inflammatory” hydroxylase (HU) by injection of fetal hemoglobin (HbF, α2γ2) (Ware and Aygun). 2009). Other effects of HU include improvement of RBC hydration, reduction of neutrophil count, etc
Two New Drugs Help Relieve Sickle Cell Disease. But Who Will Pay?
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