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Genome editing strategies for targeted correction of β-globin mutation in sickle cell disease: From bench to bedside
Henna Butt1, Shruti Sathish1, Evan London1
1Cellular and Molecular Therapeutics Branch (CMTB), National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20814, USA.
Insights
Gene editing offers promising sickle cell disease (SCD) cures by correcting the beta-globin gene (HBB). Current challenges include efficiency, off-target effects, and cost, but research continues to advance HBB correction strategies.
Area of Science:
- Hematology
- Genetics
- Molecular Biology
Background:
- Sickle cell disease (SCD) is a genetic disorder affecting red blood cell physiology, leading to severe complications across multiple organ systems.
- Current disease-modifying therapies for SCD do not fully address the disease's complexity and severity.
- Allogeneic transplantation and autologous gene therapy show promise but face challenges in achieving a universal cure.
Purpose of the Study:
- To review past, present, and future developments in gene correction strategies for sickle cell disease.
- To explore the application of various gene-editing technologies for targeted correction of the beta-globin gene (HBB) in SCD.
- To discuss the limitations and challenges associated with translating gene-editing therapies from laboratory research to clinical practice.
Main Methods:
- Review of existing literature on gene-editing technologies for SCD, including zinc-finger nucleases, TALENs, CRISPR-Cas, base editing, and prime editing.
- Analysis of both ex vivo and in vivo approaches for targeted HBB gene correction.
- Examination of the efficacy, safety, and cost-effectiveness of emerging gene-editing strategies.
Main Results:
- Gene-editing technologies demonstrate potential for targeted correction of the HBB gene in SCD.
- Ex vivo and in vivo gene-editing approaches have shown promising outcomes in preclinical and early clinical studies.
- Significant challenges remain, including achieving high mutation-correction efficiency and minimizing off-target effects.
Conclusions:
- Gene editing represents a promising frontier for curing sickle cell disease through HBB correction.
- Overcoming technical hurdles such as efficiency, off-target effects, and high therapy costs is crucial for clinical translation.
- Continued research and development in gene-editing technologies are essential to establish optimal strategies for a durable SCD cure.
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.
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