A Review of Gene Therapies for Hemoglobinopathies.

Due to the significant morbidity and mortality of hemoglobinopathies, curative options have long been pursued. The overall goal of gene therapy is to modify a patient's own hematopoietic stem cells to overcome the deleterious effects of the underlying genetic defect by gene addition, gene editing, or gene silencing. Gene addition incorporates genes with superior function than the abnormal gene; gene editing takes advantage of molecular tools such as zinc finger proteins, Transcription Activator-Like Effector Nucleases and Clustered Regularly Interspaced Short Palindromic Repeats coupled with Cas9 proteins (CRISPR-Cas9) which allow for sequence-specific breaks in DNA that disrupt gene function; and gene silencing suppresses gene expression by interference with mRNA transcription/protein translation or epigenetic modification. The majority of gene therapy strategies for hemoglobinopathies have targeted erythroid-specific BCL11A, a major regulator of fetal hemoglobin repression at the gamma-globin locus, in the normal fetal-to-adult hemoglobin switch that occurs shortly after birth. Other goals have involved the incorporation of anti-sickling globins, such as β^T87Q or βAS3. Landmark clinical trials of gene therapy in transfusion-dependent thalassemia and sickle cell disease have shown remarkable efficacy and acceptable safety and culminated in recent regulatory approvals of gene therapy for both diseases in Europe and the United States.