Editors' ChoiceHEMATOLOGY

CRISPR cuts disease course short in blood disorders

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Science Translational Medicine  06 Jan 2021:
Vol. 13, Issue 575, eabg1756
DOI: 10.1126/scitranslmed.abg1756


Gene editing for sickle cell disease and β-thalassemia results in potential curative response.

Sickle cell disease (SCD) and β-thalassemia originate from mutations in the hemoglobin gene and are among the most common hereditary diseases in the world. Their high frequency is believed to originate from a protective effect against malaria, a mosquito-borne infectious disease. However, patients carrying two mutant alleles of hemoglobin suffer from mild-to-severe blood disease. SCD primarily leads to aggregation of red blood cells leading to vaso-occlusive crises, whereas thalassemia results in anemia requiring continuous transfusions.

The recent report published by Frangoul et al. describes the first readout from a clinical trial using CRISPR-edited autologous hematopoietic stem cells in SCD and transfusion-dependent thalassemia (TDT). A single guide RNA was used in combination with Cas9 (CTX001) to induce small insertions and deletions in the erythroid enhancer region of the BCL11A gene. The protein product of this gene is responsible for repressing fetal (γ) hemoglobin in the first year of life and induces the production of adult (β) hemoglobin. Individuals carrying genetic variants in this erythroid enhancer region are protected from symptoms of SCD or thalassemia due to down-regulation of BCLA11 and consequent higher levels of γ-hemoglobin. CRISPR strategy mimics this protective effect by repressing the master switch. Patient 1 in the study suffered from TDT and received on average 34 transfusions per year. She received her last transfusion 30 days after the infusion of CTX001 and remained transfusion-independent afterward. Patient 2 suffered from severe SCD and had on average 7 vaso-occlusive crises and 3.5 hospitalizations per year. She never had these episodes after therapy. Both patients demonstrated up to 80% allelic editing in their engineered stem cells, and up-regulation of fetal hemoglobin was noted after infusion.

Although data from these patients suggest potential curative responses, there were several adverse effects during the follow-up period, some of them were classified as severe. These included pneumonia and veno-occlusive liver disease or sepsis, among others. These adverse effects were most likely related to the myeloablative conditioning before CTX001. Chemotherapeutic agents are required before such stem cell treatment, and this is a limitation of this otherwise highly efficient approach. Several questions still remain, such as clonal diversity and stability of the clinical outcome over time.

There are numerous medications under development for blood diseases; the fierce competition is an advantage for the patients. Severe disease course in blood diseases, however, can be cut short with CRISPR.

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