Novel Gene Editing for Sickle Cell Disease and β-Thalassemia

Novel gene editing treatment with exa-cel has been recently approved for treatment of severe sickle cell disease and transfusion-dependent β-thalassemia. It was six decades back that it was noticed that patients with hereditary persistence of fetal hemoglobin had a milder course of β-thalassemia and it was postulated that stimulation of production of fetal hemoglobin might provide benefits to adults with sickle cell disease and severe β-thalassemia. Later it was also shown that higher levels of fetal hemoglobin was associated with prolonged survival in these conditions. Two articles published in the New England Journal of Medicine have evaluated the role of Exagamglogene autotemcel (exa-cel) in the treatment of severe sickle cell disease and transfusion-dependent β-thalassemia. Autologous cellular therapy exagamglogene autotemcel is generated by editing an erythroid-specific enhancer of BCL11A. That is why it needs autologous bone marrow transplantation and hence quite cumbersome and expensive, with limited availability.
Exagamglogene autotemcel is designed to reactivate fetal hemoglobin synthesis by ex vivo gene editing using CRISPR-Cas9 (CRISPR-associated protein 9), the novel gene editing tool which has been recognized by a Nobel Prize. CRISPR stands for clustered regularly interspaced short palindromic repeats. Gene editing is done for autologous CD34+ hematopoietic stem and progenitor cells at the erythroid-specific enhancer region of BCL11A. BCL11A gene encodes B-cell lymphoma/leukemia 11A protein. BCL11A plays a role in the switch from γ- to β-globin expression during the transition from fetal to adult erythropoiesis. Exa-cel treatment eliminated painful vaso-occulsive crises in 97% of patients with sickle cell disease for a period of one year or more. Similarly, treatment with exa-cel preceded by myeloablation resulted in transfusion independence in 91% of transfusion-dependent β-thalassemia patients. Specificity of exa-cel in avoiding unintentional editing of other sites or off-target editing has been checked by another study published in the same issue of NEJM.
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