Abstract

Title: Comparative Meta-analysis of CRISPR Gene Editing Targets to Induced Fetal Hemoglobin (HbF) Expression in Beta-Thalassemia and Sickle Cell Disease

Authors: Quagliano, A.¹ and Prasad, S.¹

Institution: ¹Dr. Kiran C Patel College of Allopathic Medicine at Nova Southeastern University, Davie, FL 33328

            β-thalassemia and sickle cell disease (SCD) are inherited blood disorders characterized by a deficient/mutated hemoglobin due to defects in the β-globin gene. Disorders affecting the hemoglobin production can lead to transfusion dependency and associated complications such as iron overload. SCD patients are also susceptible to sickle cell crisis and serious outcomes such as avascular necrosis. Transfusion-independent management for these disorders can include the induction of fetal hemoglobin (HbF) expression. HbF expression in β-thalassemia and SCD can increase total hemoglobin production and can replace the mutated β-globin in SCD. Pharmacological agents such as hydroxyurea may be used for HbF induction, however, these effects are transient and diminish without consistent therapy. Gene targeting therapies like clustered regularly interspaced short palindromic repeats (CRISPR) have opened the door for inducing long-term expression of HbF and improving therapies for β-thalassemia and SCD patients. Of these gene targets, BCL11A (an HbF repressor) and HBG1/2 (promoter regions of the HbF genes) have been discovered to be the most promising for induction of HbF. A meta-analysis was performed to identify the gene target that is most effective in inducing HbF expression. A total of 8 studies published from 2018-2021 were identified for inclusion. Primary analysis revealed that HBG1/2 (-30.87 [-47.72, -14.01 CI]) had a moderately greater effect (Hedges’ g of 2.47 [-0.92, 5.87 CI]) in inducing HbF than BCL11A (-24.03 [-36.94, -11.12 CI). From these findings, we can conclude that HBG1/2 is a relatively more promising gene target for management of β-thalassemia and SCD by comparison to BCL11A.