Hemoglobinopathies are the most common inherited red cell disorders world-wide. Among these, sickle cell syndromes & thalassemia constitute a major public health problem. A glutamic acid to valine substitution at the 6th amino acid of the globin chain of human haemoglobin (HbA) results in formation of sickle haemoglobin (HbS). Sickle cell disease results from homozygosity for this mutation, or from a compound heterozygosity for sickle haemoglobin and β-thalassemia or another β-globin variant such as HbC, HbD, HbE, or НЬОArab.
The sickle mutation renders the haemoglobin molecule insoluble upon deoxygenation; thus, RBCs containing deoxy HbS polymer are rigid and have impaired rheologic properties. This leads to a haemolytic anaemia, an inflammatory state, painful vaso occlusive episodes, and damage to multiple organ systems with a resultant shortened life expectancy. Stroke, acute chest syndrome, priapism, pulmonary hypertension and avascular necrosis are few of the life-threatening complications.
Sickle cell anaemia is characterized by a laboratory profile of evidence of haemolytic anaemia with increases in LDH, indirect bilirubin, reticulocyte count, and a decrease in serum haptoglobin. Anaemia is usually normochromic, normocytic with a steady-state Hb level between 5 and 11 g/dL. Morphologically, classic sickle red cells are seen on blood film examination, and the marrow shows erythroid hyperplasia.
SCA can be accurately diagnosed with high-performance liquid chromatography (HPLC) and isoelectric focusing. Rapid methods, such as solubility testing and sickling of red cells using sodium metabisulfite, are less-reliable tests. Polymerase chain reaction (PCR) is the method of choice for prenatal diagnosis. Molecular genetic testing incorporated into new born screening (NBS) for SCD gives a timely correct diagnosis which permits the use of early, pre symptomatic hydroxyurea therapy and prevents infants with HbS/HPFH from receiving unnecessary medical intervention.
Over the past few decades, advances in supportive care and implementation of disease-modifying therapies, such as “anti-switching” therapies preventing switch from γ-globin to β-globin, which result in increased HbF and less HbS synthesis, and have led to an increase in life expectancy. Hydroxy urea has emerged as an effective disease-modifying agent. Novel anti-switching agents, most notably, DNA methyltransferase 1 inhibitors (5'-azactidine and decitabine) and histone deacetylase inhibitors (butyrate derivatives and others) are also used. Antiadhesive therapies that prevent interaction of sickle cells with microvascular endothelium, anti-inflammatory approaches, and modulation of haemoglobin-oxygen affinity to prevent sickling are also used.
Few months ago, US FDA has approved two milestone treatments, Casgevy (utilizing CRISPR/cas9) and Lyfgenia, the first cell-based gene therapies for the treatment of SCD in patients 12 years and older. In both the therapies patients own blood stem cells, which are modified are given back as a one-time, single dose infusion as a part of hematopoietic stem cell transplant (HSCT). The patients who received these gene therapies are being followed up to evaluate safety and effectiveness. However, to date, the only curative therapy remains allogeneic HSCT.
Reference:
Williams hematology 9th edition. Disorders of hemoglobin structure: Sickle cell anemia and related abnormalities. Chapter 49.
Quinn et al. Clinical utility of the addition of molecular genetic testing to newborn screening for sickle cell anemia. Frontiers in medicine. 2021; 8:734305.
FDA news release. FDA approves first gene therapies to treat patients with sickle cell disease. 8th December, 2023.
