CRISPR-Cas9: a step toward a cure for sickle cell disease

Abstract

Background: Sickle cell disease (SCD) is an inherited blood disorder caused by a GAG to GTG mutation in the 6th codon of the Hbβ gene, resulting in a glutamine to valine substitution in the β-chain of hemoglobin. This leads to the production of abnormal hemoglobin molecules. Currently, there are four Food and Drug Administration (FDA) approved drugs to manage acute complications, and blood transfusions are used in some cases. Hematopoietic stem cell transplantation (HSCT) from a matched related donor is the only curative therapy available. Gene therapy, specifically using CRISPR-Cas9, is being studied as another curative option. CRISPR-Cas9, a powerful genome editing system that emerged in 1987, acts as molecular scissors that can precisely cut Deoxyribonucleic Acid (DNA) strands to add or remove specific sequences.
Aim: This review examines how CRISPR-Cas9 technology can be used to treat sickle cell disease, emphasizing its mechanism, current developments in clinical practice, and potential as a gene-editing cure.
Methodology: The review utilized about 30 primary studies sourced from various electronic databases, including Semantic Scholar, PubMed and Google Scholar. The selection criteria focused on research related to CRISPR-Cas9 technology used in the treatment of sickle cell disease. Boolean operators were utilized to refine the search and ensure relevant studies were obtained. It will examine how CRISPR-Cas9 technology can be used to treat sickle cell disease, emphasizing its mechanism, current developments in clinical practice, and potential as a gene-editing cure. The review focuses on the use of CRISPR-Cas9 technology to treat SCD by either correcting the HbS mutation or promoting fetal hemoglobin (HbF) production. The most common clinical approach emphases on boosting HbF by downregulating the BCL11A transcription factor, a validated repressor of HbF. Disrupting a BCL11A erythroid-specific enhancer with CRISPR-Cas9 followed by autologous HSCT has shown to elevate HbF levels and reduce SCD symptoms. On December 8, 2023, the FDA approved CASGEVY™, the first cell-based CRISPR-Cas9 gene therapy for treating SCD in patients aged 12 and older with recurrent vaso-occlusive crises.
Result: CASGEVY™ inactivates BCL11A to convert abnormal HbS in blood stem cells into HbF. It offers a more sustainable and comprehensive solution by targeting the genetic basis of SCD. Its use's limitations and ethical issues are also covered in the review.
Conclusion: A novel method of treating sickle cell disease (SCD) is provided by CRISPR-Cas9, which either directly corrects the HbS mutation or stimulates the synthesis of fetal haemoglobin (HbF).