DISCOVERIES OF GENE EDITING USING CRISPR-CAS9 FOR THE TREATMENT OF SICKLE CELL DISEASE: A LITERATURE REVIEW

Abstract

Introduction/objectives: Sickle cell disease (SCD) is the most common monogenic blood disorder worldwide, causing reduced life expectancy to the patients. The innovative CRISPR-Cas9 gene-editing technology, pioneered by Jennifer Doudna and Emmanuelle Charpentier, has emerged as a potential curative treatments for SCD. This review aims to comprehensively explore the latest advancements in CRISPR-Cas9 for SCD treatment. Methods: This is a literature review carried out through the analysis of articles published between 2016 and 2024 obtained through a search in the PubMed database. The descriptors used were: (Sickle cell disease) AND (CRISPR). A total of 12 articles were selected based on these criteria. Results: The development and regulatory approvals of therapeutic CRISPR-Cas9 for patients with SCD has been crucial in improving curative treatment options. This gene therapy involves targeting the BCL11A erythroid-specific enhancer to induce the expression of fetal hemoglobin (HbF), which can alleviate the clinical manifestations of this hemoglobinopathy. This approach aims to correct the genetic defect at its source, offering a potential functional cure for SCD. Discussion: Sickle cell disease (SCD) is a group of inherited red blood cell disorders characterized by the production of abnormal hemoglobin, specifically hemoglobin S (HbS). This genetic defect is caused by a point mutation in the β-globin gene on chromosome 11, and leads the hemoglobin molecules to polymerize under low oxygen conditions, resulting in the deformation of red blood cells into a rigid, sickle shape. Besides hemoglobin polymerization, the pathophysiology of SCD involves: vaso-occlusive crisis, hemolytic anemia, splenic dysfunction and organ damage. This can result in ischemia, tissue damage, and severe pain. Chronic vaso-occlusion and microinfarctions can cause damage to various organs, including the liver, kidneys, lungs, and bones. SCD is managed through a combination of symptomatic treatments, disease-modifying therapies, but curative treatment options for SCD remain very limited. Symptomatic treatments include hydroxyurea, which increases fetal hemoglobin (HbF) levels, reducing vaso-occlusive crises; L-glutamine, Voxelotor and Crizanlizumab. The only established curative treatment was allogeneic hematopoietic stem cell transplantation (HSCT), but this option is limited by donor availability and risks of graft-versus-host disease. Therefore, CRISPR-Cas9 technology has a great potential as a curative treatment of SCD, once his approach has shown promising results in clinical trials, with patients achieving high levels of HbF and significant clinical improvements, including the elimination of vaso-occlusive episodes. These studies led to important regulatory agents approvals in Europe and the USA. Conclusion: CRISPR-Cas9 therapy has a great potential to provide a durable and potentially curative treatment for SCD. By reactivating HbF production, CRISPR-Cas9 can mitigate the pathophysiological effects of HbS polymerization, thereby reducing the frequency of vaso-occlusive crises and improving overall hematologic parameters. This represents a significant advancement over traditional treatments, which primarily focus on symptom management and reducing complications, leading to significant clinical benefits and offering a promising therapeutic avenue for this debilitating disease.