Revolutionizing Sickle Cell Disease Treatment: The Promise of Gene Therapy and CRISPR-Cas9

Sickle cell disease (or SCD) is a haemoglobinopathy disorder representing sickle-shaped haemoglobin protein (HbS), anaemia due to haemolysis, infections, vaso occlusion and most of the time end organ damage.?In the normal scenario, the haemoglobin molecules consist of two α polypeptide chains and two β polypeptide chains.?In SCD patients, the red blood cells, usually disc-shaped, get metamorphosed into sickle shape due to haemoglobin forming stiff rods within the red blood cells, leading to restricted movement and bursting of the RBCs causing anaemia. A single point mutation in the sixth codon of the beta-globin chain of haemoglobin molecule results in glutamic acid being substituted by valine causing the formation of abnormal tetramer HbS (different from normal adult haemoglobin HbA) that tends to polymerize during dehydration or acidosis. Vaso occlusion due to the sticking of sickle-shaped RBCs to the walls of blood vessels, causes obstruction of blood vessels, reduced blood flow and oxygen deprivation to tissues causing pain crises. Sickle cell disease, though affecting millions of people globally and showcasing hemolysis and tissue ischemia, the incidence is particularly noted in high numbers in Africa, the Mediterranean regions, the Middle East and India with high mortality rates due to inaccessibility to affordable drugs.

SCD is an umbrella term encircling individuals possessing HbS as the major form of haemoglobin. Genotypically sickle cell disease can be classified into Haemoglobin SS(HbSS), Haemoglobin SC(HbSC), Haemoglobin beta-thalassemia (HbS, which is further classified into subtypes Plus [HbS beta +] and zero [HbS beta 0], Haemoglobin SD (HbSD), Haemoglobin SE (HbSE) and Haemoglobin SO (HbSO). ?SCD can be phenotypically subdivided into viscosity-vaso-occlusion and hemolysis-endothelial dysfunction. These classifications enable easy and quick knowledge of the pathobiology of the disease aiding in the development and administration of effective therapies that are specific to the disease condition. Conventional treatments that have been in use relieve symptoms of SCD and include administration of antibiotics, analgesics, HbS polymerisation inhibitors, pain relievers, hydroxyurea, vitamins, antihypertensives, blood transfusions etc. These therapies modify the disease condition by managing symptoms to a great extent.

A permanent solution intending the genetic mutation and tackling reiterative episodes of acute microvascular occlusion and chronic haemolytic anaemia needs to be in place. Monoclonal Antibodies (MAbs)against P-selectin glycoprotein reduce the vaso-occlusive crises. Haematopoietic stem cell transplantation using an allogeneic transplant from an HLA-matched sibling is considered curative but risks and serious side effects( like finding a close donor match, graft loss, graft versus host disease etc.) outweigh the curative side. Gene therapy has carved its path as a potential treatment option by modifying or correcting the sickle gene, restoration of HbA function, and high fetal haemoglobin (HbF) expression. CRISPR-Cas 9 has revolutionized the DNA editing process and obtained approval from the USFDA in December 2023 to be used for patients with sickle cell disease and transfusion-dependent beta-thalassemia. Administration of autologous gene therapy eliminates the need to find a donor match.

Though the genetic cause of SCD was deciphered almost six decades ago, the average life expectancy of patients has not increased, as treatment options remain limited and SCD remains a public health problem worldwide in terms of frequency, morbidity, quality of life and mortality. CRISPR CAS 9 targets the repair of disease-causing mutations through correction, deletion, and addition, of the specific sequences through Double Strand Breaks ( DSBs), and non-homologous end joining (NHEJ) or homology-directed repair (HDR). High efficacy and safety combined with scalability will make gene-editing strategy a clinically promising approach, providing a key solution to years of medical need.

DDE with its vast experience as a turnkey provider in the field of biopharmaceuticals, caters to multidisciplinary approaches and promotes innovation. High costs of production in these novel therapeutic fields make the process inaccessible to a major population. Our bioreactors would focus on scalable technologies, thereby assisting in a significant reduction in production costs and overall treatment costs in the long term, opening ways to an affordable option. Though approved by regulatory authorities, the technology is still in its infancy needing collaborative funding in research, boosting technological development and innovation for fruition translation into the manufacturing arena. As the theme for World Sickle Cell Day, let us “Hope through progress: advancing sickle cell care globally” and expand research on this innovative technology, increasing life expectancy and quality of life of patients globally.

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