Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease

Abstract

Autologous hematopoietic stem cell (HSC)-targeted gene therapy provides a one-time cure for various genetic diseases including sickle cell disease (SCD) and β-thalassemia. SCD is caused by a point mutation (20A > T) in the β-globin gene. Since SCD is the most common single-gene disorder, curing SCD is a primary goal in HSC gene therapy. β-thalassemia results from either the absence or the reduction of β-globin expression, and it can be cured using similar strategies. In HSC gene-addition therapy, patient CD34+ HSCs are genetically modified by adding a therapeutic β-globin gene with lentiviral transduction, followed by autologous transplantation. Alternatively, novel gene-editing therapies allow for the correction of the mutated β-globin gene, instead of addition. Furthermore, these diseases can be cured by γ-globin induction based on gene addition/editing in HSCs. In this review, we discuss HSC-targeted gene therapy in SCD with gene addition as well as gene editing.

CRISPR–Cas9 Gene Editing: Curing Genetic Diseases by Inherited Epigenetic Modifications

“…One of the key studies demonstrating the clinical potential of CRISPR-Cas9 for treating sickle cell anemia was conducted by Germino-Watnick et al 47 In this study, hematopoietic stem and progenitor cells (HSPCs) were obtained from sickle cell anemia patients and subjected to CRISPR-Cas9 gene editing to correct the mutation in the β-globin gene. The edited HSPCs were then infused back into the patients, aiming to restore normal red blood cell function.…”

“…Germino-Watnick et al 47 Editing hematopoietic stem and progenitor cells (HSPCs) to treat Sickle Cell Anemia CRISPR-Cas9's therapeutic promise in treating sickle cell anemia.…”

Site-specific genome editing in treatment of inherited diseases: possibility, progress, and perspectives

“…Several gene targets involved in regulating the β-globin gene or γ-globin (forming fetal Hb, abbreviated as HbF), which has anti-sickling effects, have been proposed and proved useful [ 177 , 178 ]. One of the employed strategies is gene addition by lentivirus in patient CD34 + HSCs that are widely tested in clinical trials and reviewed elsewhere [ 179 ].…”

Finding Consensus miRNAs Silencing KLF1 Expression as A Promising Therapeutic Option of Sickle Cell Anemia

“…In gene addition, normal HbA is introduced via lentiviral vectors to SCA patients in order to compensate the reduced oxygen-carriage function of HbS so that new (HbA) and old (HbS) are co-present with near-normal therapeutic status. This mode of gene therapy is realized to be one-time cure of SCA and safer than other methods [9]. Likewise, in gene editing technology the mutated HbS within hematopoietic stem cells is genetically engineered ex vivo and then returned back to the body [10].…”