Ivy Wong

Introduction: Beta thalassemia is among the most common monogenic diseases in the world, with an annual diagnosis of 600,000.³ It is a genetic disorder with a mutation in the adult HBB gene on chromosome 11, which encodes for the production of B-globin.² The mutation leads to reduced or absent hemoglobin levels, which cause anemia, jaundice, failure to thrive, and other comorbidities.⁶ Current treatment for beta-thalassemia consists of constant blood transfusions with iron chelation and hematopoeitic stem cell transplant. However, there are many complications with bone marrow transplants including little donor availability and risk of graft-vs-host disorders.^1.3 Gene therapy has been an evolving method incorporated into medical treatments today, with CRISPR-Cas9 being a topic of interest. Using the CRISPR-Cas9 editing system would allow patients to use their own HSPCs, avoid the risks of receiving donor marrow, and achieve clinically significant levels of functional hemoglobin. Methods: Current methods target the BCL11A gene, which suppresses fetal hemoglobin expression in adults.³ It has been found that polymorphisms that allow for the expression of fetal hemoglobin into adulthood exhibit less severe symptomology and better mortality and morbidity outcomes in patients with beta-thalassemia.⁴ Hematopoietic stem cells are obtained from the patient, edited with CRISPR-Cas9 ex-vivo using a non-homologous end-joining method at the BCL11A, therefore downregulating it. Edited cells are reinfused into the patient after myeloablation and hemoglobin levels are monitored.³ Results: The results from the study show a marked increase in fetal hemoglobin levels 21 months after reinfusion and the patient was able to stop receiving blood transfusions. Adverse events recorded were majority of grade 1 or 2, with one serious adverse event of pneumonia being resolved by day 39 of reinfusion.³ Conclusion: The results from the study provide a promising future for the use of CRISPR-Cas9 as a therapy for transfusion-dependent thalassemia. Further monitoring for long-term effects is still needed and studies with a larger pool of patients are also being developed, providing more research on the applicability of this method of gene therapy.

1. Bloomer H, Smith R, Hakami W, Larochelle A. Genome editing in human hematopoietic stem and progenitor cells via CRISPR-Cas9-mediated homology-independent targeted integration. Molecular Therapy. 2021;29(4):1611-1624. doi:10.1016/j.ymthe.2020.12.010
2. Chen Y, Wen R, Yang Z, Chen Z. Genome editing using CRISPR/Cas9 to treat hereditary hematological disorders. Gene Therapy. Published online March 9, 2021. doi:10.1038/s41434-021-00247-9
3. Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N Engl J Med. 2021;384(3):252-260. doi:10.1056/NEJMoa2031054
4. Razak SAA, Murad NAA, Masra F, et al. Genetic Modifiers of Fetal Haemoglobin (HbF) and Phenotypic Severity in β-Thalassemia Patients. Curr Mol Med. 2018;18(5):295-305. doi:10.2174/1566524018666181004121604
5. Thein SL. Molecular basis of β thalassemia and potential therapeutic targets. Blood Cells, Molecules, and Diseases. 2018;70:54-65. doi:10.1016/j.bcmd.2017.06.001
6. Viprakasit V, Ekwattanakit S. Clinical Classification, Screening and Diagnosis for Thalassemia. Hematology/oncology clinics of North America. 2018;32(2):193-211. doi:10.1016/j.hoc.2017.11.006