CRISPR/Cas9 gene therapy in sickle cell disease. IS IT SAFE?
CRISPR/Cas9 gene therapy in sickle cell disease. IS IT SAFE?
Mahsa Asghari,1,*Elham Khakshour,2
1. VaseiClinical Research Development Unit, Sabzevar University of Medical Sciences, Sabzevar, Iran 2. Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
Introduction: Sickle cell disease (SCD) is the most prevalent monogenic hematologic disorder, characterized by congenital hemolytic anemia resulting from an inherited point mutation in the β-globin gene on chromosome 11. Despite the identification of the genetic basis of SCD in 1957, treatment options remain limited. Hematopoietic stem cell transplantation (HSCT) was seen as a potential cure, but only 15% of donors were suitable. However, ex vivo engineering of autologous hematopoietic stem and progenitor cells, followed by transplantation of genetically modified cells, may offer a permanent cure for all patients, eliminating dependence on suitable donors and the risk of graft-vs-host disease. The advent of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) systems have transformed the field by allowing precise targeting of genes. This study focused on clinical trials conducted on SCD patients using the CRISPR/Cas9 gene editing method and its safety.
Methods: Data was obtained from MEDLINE, Scopus, and Web of Science databases via the following keywords: sickle cell disease, SCD, hemoglobinopathy, CRISPR/Cas9, CRISPR, gene editing, gene therapy, complication, and side effects.
Results: After searching the terms mentioned, over 60 articles were selected for the subsequent study. Twelve articles (including over 200 patients) were selected for final examinations. We found out that 7 major clinical trials are being conducted worldwide investigating the efficacy of CRISPR/Cas9 for SCD treatment by targeting BCL11A and HBB genes. As the results showed, all patients demonstrated clinically meaningful increases in total Hb and HbF, which occurred early and have been maintained over time, and almost all patients were free from vaso-occlusive crises for at least 12 consecutive months. Several adverse effects were reported after engraftment of gene-modified hematopoietic stem cells, including nausea, vomiting, low blood cell counts, and organ toxicities, particularly in older patients; however, all these adverse effects were mentioned as busulfan-based myeloablative conditioning-related conditions. To date, no evidence of serious complications such as any malignancies has been reported.
Conclusion: Unlike older methods that used viral vectors potentially leading to acute side effects like leukemia by affecting genes related to cell growth and maturation, CRISPR/Cas9 demonstrates promising results for treating hemoglobinopathies, including sickle cell disease and major β-thalassemia. While this treatment is novel, further monitoring is necessary to address any future complications.