Gene Therapy for β-Hemoglobinopathies: From Discovery to Clinical Trials

Eva Eugenie Rose Segura; Paul George Ayoub; Kevyn Lopez Hart; Donald Barry Kohn

doi:10.3390/v15030713

Gene Therapy for β-Hemoglobinopathies: From Discovery to Clinical Trials

Viruses. 2023 Mar 9;15(3):713. doi: 10.3390/v15030713.

Authors

Eva Eugenie Rose Segura¹, Paul George Ayoub², Kevyn Lopez Hart³, Donald Barry Kohn^{4

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Affiliations

¹ Molecular Biology Interdepartmental Doctoral Program, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
² Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
³ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁴ Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁵ Department of Pediatrics (Hematology/Oncology), David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁶ Eli and Edythe Broad Center for Stem Cell Research and Regenerative Medicine, University of California, Los Angeles, CA 90095, USA.

Abstract

Investigations to understand the function and control of the globin genes have led to some of the most exciting molecular discoveries and biomedical breakthroughs of the 20th and 21st centuries. Extensive characterization of the globin gene locus, accompanied by pioneering work on the utilization of viruses as human gene delivery tools in human hematopoietic stem and progenitor cells (HPSCs), has led to transformative and successful therapies via autologous hematopoietic stem-cell transplant with gene therapy (HSCT-GT). Due to the advanced understanding of the β-globin gene cluster, the first diseases considered for autologous HSCT-GT were two prevalent β-hemoglobinopathies: sickle cell disease and β-thalassemia, both affecting functional β-globin chains and leading to substantial morbidity. Both conditions are suitable for allogeneic HSCT; however, this therapy comes with serious risks and is most effective using an HLA-matched family donor (which is not available for most patients) to obtain optimal therapeutic and safe benefits. Transplants from unrelated or haplo-identical donors carry higher risks, although they are progressively improving. Conversely, HSCT-GT utilizes the patient's own HSPCs, broadening access to more patients. Several gene therapy clinical trials have been reported to have achieved significant disease improvement, and more are underway. Based on the safety and the therapeutic success of autologous HSCT-GT, the U.S. Food and Drug Administration (FDA) in 2022 approved an HSCT-GT for β-thalassemia (Zynteglo™). This review illuminates the β-globin gene research journey, adversities faced, and achievements reached; it highlights important molecular and genetic findings of the β-globin locus, describes the predominant globin vectors, and concludes by describing promising results from clinical trials for both sickle cell disease and β-thalassemia.

Keywords: autologous hematopoietic stem-cell transplant; clinical trials; gene therapy; lentiviral vectors; sickle cell disease; β-globin genes; β-hemoglobinopathies; β-thalassemia.

Publication types

Review
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anemia, Sickle Cell* / genetics
Anemia, Sickle Cell* / therapy
Genetic Therapy / methods
Genetic Vectors / genetics
Hematopoietic Stem Cell Transplantation* / methods
Hemoglobinopathies* / genetics
Hemoglobinopathies* / therapy
Humans
beta-Globins / genetics
beta-Thalassemia* / genetics
beta-Thalassemia* / therapy

Substances

beta-Globins

Abstract

Publication types

MeSH terms

Substances

Grants and funding