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Molecular Diagnosis & Therapy

, Volume 23, Issue 2, pp 173–186 | Cite as

Gene Therapy for Beta-Hemoglobinopathies: Milestones, New Therapies and Challenges

  • Valentina Ghiaccio
  • Maxwell Chappell
  • Stefano Rivella
  • Laura BredaEmail author
Review Article

Abstract

Inherited monogenic disorders such as beta-hemoglobinopathies (BH) are fitting candidates for treatment via gene therapy by gene transfer or gene editing. The reported safety and efficacy of lentiviral vectors in preclinical studies have led to the development of several clinical trials for the addition of a functional beta-globin gene. Across trials, dozens of transfusion-dependent patients with sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT) have been treated via gene therapy and have achieved reduced transfusion requirements. While overall results are encouraging, the outcomes appear to be strongly influenced by the level of lentiviral integration in transduced cells after engraftment, as well as the underlying genotype resulting in thalassemia. In addition, the method of procurement of hematopoietic stem cells can affect their quality and thus the outcome of gene therapy both in SCD and TDT. This suggests that new studies aimed at maximizing the number of corrected cells with long-term self-renewal potential are crucial to ensure successful treatment for every patient. Recent advancements in gene transfer and bone marrow transplantation have improved the success of this approach, and the results obtained by using these strategies demonstrated significant improvement of gene transfer outcome in patients. The advent of new gene-editing technologies has suggested additional therapeutic options. These are primarily focused on correcting the defective beta-globin gene or editing the expression of genes or genomic segments that regulate fetal hemoglobin synthesis. In this review, we aim to establish the potential benefits of gene therapy for BH, to summarize the status of the ongoing trials, and to discuss the possible improvement or direction for future treatments.

Notes

Compliance with Ethical Standards

Conflict of interest

LB, VG and MC declare no conflict of interest. SR is a consultant for Ionis Pharmaceuticals.

Funding

This review was made possible through the collaboration of LB and SR in the THALAssaemia MOdular Stratification System for personalized therapy of β-thalassemia (THALAMOSS), European Community: FP7-HEALTH-2012-INNOVATION. This work is supported by grants from the National Institutes of Health (NIDDK-R01DK090554 and NIDDK-R01DK095112 to S.R.). The authors gratefully acknowledge the generous support by the Jean, Schejola and Di Gaetano families and the Children’s Hospital of Philadelphia Foundation.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Valentina Ghiaccio
    • 1
  • Maxwell Chappell
    • 1
  • Stefano Rivella
    • 1
  • Laura Breda
    • 1
    Email author
  1. 1.Hematology DivisionChildren’s Hospital of PhiladelphiaPhiladelphiaUSA

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