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A promising gene therapy for the treatment of sickle cell disease and “transfusion-dependent” beta-thalassemia

​In order to fight sickle cell disease and beta-thalassemia, two common genetic diseases affecting red blood cells, the AP-HP, the University of Paris, Inserm (Imagine Institute), Paris-Est Créteil University and the CEA-Jacob have conducted a clinical study utilizing the transplantation of a patient's own genetically modified stem cells. A phase I/II trial with bluebird bio as the sponsor has been completed.

Published on 28 January 2022

Sickle cell disease and β-thalassemia are chronic anemias caused by mutations in the gene that encodes the beta (β) chain of adult hemoglobin (HbA).

Transfusion-dependent β-thalassemia is characterized by the severely reduced synthesis of β-globin chains or the total lack thereof, resulting in inefficient red blood cell manufacture and severe anemia requiring regular and frequent red blood cell transfusions. The ensuing accumulation of iron can cause heart failure, cirrhosis, liver cancer and multiple endocrine abnormalities.

Sickle cell disease results from the mutation of an amino acid in the β-globin chain which leads to the polymerization of hemoglobin. This in turn causes painful vaso-occlusive crises and the premature destruction of red blood cells (hemolysis). In addition to anemia, microvessel obstruction and vascular compromise can damage vital organs such as the lungs, kidneys, central nervous system and heart, reducing the life expectancy of patients.

Until now, the only curative option has been the transplantation of hematopoietic stem cells (i.e. those that produce blood cells). This approach gives very good results when there is an HLA-matched sibling donor. Unfortunately, less than 20% of patients can benefit from this treatment. The use of partially matched donors, on the other hand, results in significant long-term morbidity, especially in older patients.

Gene therapy removes the risk of immunological toxicity

A technique intended for everyone, gene therapy uses the transplantation of stem cells taken from the patient and then genetically modified. There is little risk of immunological toxicity since no immunosuppressive treatment is required. It can be provided without delay, as the patient is his or her own donor.

Gene therapy by "gene addition" is the first strategy to have emerged in this application. It employs the ability of lentiviral vectors to transfer complex genetic information into the genome of hematopoietic stem cells.

The lentiviral vector used in the clinical trial was developed by a team from the CEA-Jacob (directed by Professor Philippe Leboulch). It allows the synthesis of a genetically modified form of the β-globin chain (βT87Q), which has a dual advantage:

  • it has an "anti-sickle cell" property
  • it can be assayed specifically in the blood of β-thalassemic and sickle cell patients

 A promising clinical trial

 In the clinical trial, a lentiviral gene therapy was administered to:

  • four β-thalassemic patients
  • three patients with sickle cell disease, 13 to 21 years old 

The results are promising:

  • the β-thalassemia patients were rapidly withdrawn from transfusions, and showed clear improvements in iron overload as well as corrections in the biological parameters related to chronic anemia
  • two of the three sickle cell patients experienced remission of clinical symptoms and the correction of biological parameters, while the third one saw a decrease in the rate of transfusions

These results were maintained throughout patient follow-up (more than four and a half years for three patients). No side effects related to the use of the lentiviral vector were observed.

 The long-term results suggest a nuanced conclusion for each of the diseases:

  • gene therapy by gene addition has become a curative option for β-thalassemia, and is potentially applicable to all patients lacking a matched hematopoietic stem cell donor
  • in the case of sickle cell disease, the correction of biological parameters related to chronic anemia in two out of the three patients is proof of principle of its effectiveness, and paves the way for introducing further improvements aimed at achieving the same result in all treated patients

This work was the subject of a press release.

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