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      Emerging Genetic Therapy for Sickle Cell Disease.

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          Abstract

          The genetic basis of sickle cell disease (SCD) was elucidated >60 years ago, yet current therapy does not rely on this knowledge. Recent advances raise prospects for improved, and perhaps curative, treatment. First, transcription factors, BCL11A and LRF/ZBTB7A, that mediate silencing of the β-like fetal (γ-) globin gene after birth have been identified and demonstrated to act at the γ-globin promoters, precisely at recognition sequences disrupted in rare individuals with hereditary persistence of fetal hemoglobin. Second, transformative advances in gene editing and progress in lentiviral gene therapy provide diverse opportunities for genetic strategies to cure SCD. Approaches include hematopoietic gene therapy by globin gene addition, gene editing to correct the SCD mutation, and genetic manipulations to enhance fetal hemoglobin production, a potent modifier of the clinical phenotype. Clinical trials may soon identify efficacious and safe genetic approaches to the ultimate goal of cure for SCD.

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          Author and article information

          Journal
          Annu. Rev. Med.
          Annual review of medicine
          Annual Reviews
          1545-326X
          0066-4219
          January 27 2019
          : 70
          Affiliations
          [1 ] Dana Farber/Boston Children's Cancer and Blood Disorders Center, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA; email: Daniel.Bauer@childrens.harvard.edu.
          [2 ] Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA; email: Stuart_Orkin@dfci.harvard.edu.
          Article
          10.1146/annurev-med-041817-125507
          30355263
          d005e3f5-ae1a-46b6-9293-d43b5368fd0c
          History

          BCL11A,CRISPR/Cas9,HbF,LRF/ZBTB7A,fetal hemoglobin,gene therapy,sickle cell disease

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