Innovative Therapies for Hemoglobin Disorders
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REVIEW ARTICLE
Innovative Therapies for Hemoglobin Disorders Karine Sii‑Felice1 · Olivier Negre1,2,3 · Christian Brendel2 · Alisa Tubsuwan4 · Eglantine Morel‑à‑l’Huissier1 · Camille Filardo1 · Emmanuel Payen1
© Springer Nature Switzerland AG 2020
Abstract β-Globin gene transfer has been used as a paradigm for hematopoietic stem cell (HSC) gene therapy, but is subject to major difficulties, such as the lack of selection of genetically corrected HSCs, the need for high-level expression of the therapeutic gene, and cell-specific transgene expression. It took more than 40 years for scientists and physicians to advance from the cloning of globin gene and discovering globin gene mutations to improving our understanding of the pathophysiological mechanisms involved, the detection of genetic modifiers, the development of animal models and gene transfer vectors, comprehensive animal testing, and demonstrations of phenotypic improvement in clinical trials, culminating in the authorization of the first gene therapy product for β-thalassemia in 2019. Research has focused mostly on the development of lentiviral gene therapy vectors expressing variants of the β-globin gene or, more recently, targeting a γ-globin repressor, some of which have entered clinical testing and should soon diversify the available treatments and promote price competition. These results are encouraging, but we have yet to reach the end of the story. New molecular and cellular tools, such as gene editing or the development of induced pluripotent stem cells, are being developed, heralding the emergence of alternative products, the efficacy and safety of which are being studied. Hemoglobin disorders constitute an important model for testing the pros and cons of these advanced technologies, some of which are already in the clinical phase. In this review, we focus on the development of the advanced products and recent technological innovations that could lead to clinical trials in the near future, and provide hope for a definitive cure of these severe conditions.
Key Points Advances in the development of lentiviral gene therapies in hematopoietic stem cells have led to clinical benefits in several patients with β-thalassemia and sickle cell disease. Karine Sii-Felice and Olivier Negre contributed equally.
Gene editing approaches for hemoglobinopathies are exciting and have already started to transition from lab to clinic.
* Emmanuel Payen [email protected] 1
Division of Innovative Therapies and UMR 1184 IMVA‑HB, Institute of Biology François Jacob, CEA, INSERM, ParisSaclay University, CEA Fontenay aux Roses, 18 route du Panorama, 92260 Fontenay aux Roses, France
1 Introduction
2
Dana‑Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA
1.1 Hemoglobin Disorders
3
Biotherapy Partners SAS, Paris, France
4
Institute of Molecular Biosciences, Mahidol University, Salaya, Phutthamonthon District 73170, Nakhon Pathom, Thailand
β-Hemoglobin disorders are the most common single-gene disorders wo
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