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Publications

Journal Article Review Ppublish

PubMed: 40165374 DOI: 10.1016/j.ymthe.2025.03.047

Genome editing strategies for targeted correction of β-globin mutation in sickle cell disease: From bench to bedside.

Mol Ther 33(5):2154-2171

Authors: Henna Butt, Shruti Sathish, Evan London, Taylor Lee Johnson, Khaled Essawi, Alexis Leonard, John F Tisdale, Selami Demirci

Affiliations

  • Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA.
  • Department of Medical Laboratory Technology, College of Applied Medical Sciences, Jazan University, Gizan 45142, Saudi Arabia.
  • Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA.
  • Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA.

Abstract

Sickle cell disease (SCD) includes a range of genotypes that result in a clinical syndrome, where abnormal red blood cell (RBC) physiology leads to widespread complications affecting nearly every organ system. Treatment strategies for SCD can be broadly categorized into disease-modifying therapies and those aimed toward a cure. Although several disease-modifying drugs have been approved, they do not fully address the complexity and severity of SCD. Recent advances in allogeneic transplantation and autologous gene therapy show promising outcomes in terms of efficacy and safety. While these approaches have improved the lives of many patients, achieving a durable and comprehensive cure for all remains challenging. To address this, gene-editing technologies, including zinc-finger nucleases, TALENs, CRISPR-Cas, base editing, and prime editing, have been explored both ex vivo and in vivo for targeted correction of the β-globin gene (HBB) in SCD. However, direct correction of HBB and its translation from the laboratory to the clinic presents ongoing limitations, with challenges involved in achieving robust mutation-correction efficiency, off-target effects, and high costs of therapies. The optimal strategy for curing SCD remains uncertain, but several promising approaches are emerging. This review touches on past, present, and future developments in HBB correction.

MeSH

Cells, Genes, Anemia, Sickle Cell, Genome, Gene Editing, Globins, Therapeutics, Mutation, Genetic Therapy