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Hum Mol Genet. 2019 Oct 1;28(R1):R24-R30. doi: 10.1093/hmg/ddz172.

Gene therapy of hemoglobinopathies: progress and future challenges.

Author information

1
Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia (CHOP), Philadelphia, PA, USA.
2
Laboratory of chromatin and gene regulation during development, INSERM UMR1163, Paris, France.
3
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
4
Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
5
Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France.
6
University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
7
Cell and Molecular Biology affinity group (CAMB), University of Pennsylvania.
8
Penn Center for Musculoskeletal Disorders, CHOP, Philadelphia, PA, USA.
9
INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.

Abstract

Recently, gene therapy clinical trials have been successfully applied to hemoglobinopathies, such as sickle cell disease (SCD) and β-thalassemia. Among the great discoveries that led to the design of genetic approaches to cure these disorders is the discovery of the β-globin locus control region and several associated transcription factors, which determine hemoglobin switching as well as high-level, erythroid-specific expression of genes at the ß-globin locus. Moreover, increasing evidence shows that lentiviral vectors are efficient tools to insert large DNA elements into nondividing hematopoietic stem cells, showing reassuring safe integration profiles. Alternatively, genome editing could restore expression of fetal hemoglobin or target specific mutations to restore expression of the wild-type β-globin gene. The most recent clinical trials for β-thalassemia and SCD are showing promising outcomes: patients were able to discontinue transfusions or had reduced transfusion requirements. However, toxic myeloablation and the high cost of current ex vivo hematopoietic stem cell gene therapy platforms represent a barrier to a widespread application of these approaches. In this review, we summarize these gene therapy strategies and ongoing clinical trials. Finally, we discuss possible strategies to improve outcomes, reduce myeloablative regimens and future challenges to reduce the cost of gene therapy platform.

PMID:
31322165
DOI:
10.1093/hmg/ddz172

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