Sickle cell disease: gene therapy efficacy depends on degree of host inflammation

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Sickle cell anemia is a hereditary genetic disease affecting red blood cells: a simple mutation results in the production of misshaped red blood cells known as sickle cells. Red blood cells are derived from hematopoietic stem cells (HSC), which are capable of multiplying very actively before becoming mature red blood cells. Correcting the mutation in these cells means that “normal” red blood cells can be produced, and the disease cured. To achieve this, researchers at Institut Imagine and the Biotherapy Department from Hôpital Necker-Enfants malades genetically modified HSCs from sickle cell patients in the laboratory, before reinfusing them. The patients were followed by the teams for 2 to 3 years to confirm the absence of side effects and the degree of efficacy of this gene therapy.

The results, recently published in Nature Communications, indicate that this new therapy is safe, with no side effects in the years following transplantation. However, its efficacy is variable and depends not only on the number of HSCs transplanted, but also on the host's inflammatory state and its impact on the biology of its stem cells. These data show that it is possible to assess the quality of these cells prior to implantation, thanks to the use of new single-cell analysis technologies enabling fine characterization of this rare population of cells. This study represents a major step forward in the development of a safe and effective gene therapy to treat sickle cell disease, the “most common of rare diseases”.

Sickle cell disease is a widespread genetic disorder in which a point mutation in the HBB gene affects the hemoglobin in red blood cells. This form of hemoglobin, known as sickle cell hemoglobin (HbS), accumulates in the red blood cells and causes them to become misshaped, taking on a sickle shape. These deformed red blood cells lead to anemia, painful seizures and an increased risk of infection. Although current treatments have greatly increased the life expectancy of affected patients, they are still limited.

Autologous (patient-derived) hematopoietic stem cells (HSC), which reside in the bone marrow and are the source of all blood cells, can be genetically modified before being retransplanted into patients: this protocol is a promising therapeutic option for patients who do not have a suitable donor.

This treatment has already been used in a clinical trial with patients suffering from β-thalassemia, another genetic hematological disease. Researchers at Institut Imagine (Inserm, AP-HP, Université Paris Cité) and the Biotherapy Department at Hôpital Necker-Enfants malades AP-HP have adapted the genetic vector developed in this trial for use in sickle cell gene therapy. This new vector, called DREPAGLOBE, enables the expression of “healthy” β-globin (the component of hemoglobin) and reduces the rate of sickle cell red blood cells by up to 50%.

Following production and validation of this therapeutic vector, a clinical trial was launched in November 2019 at Necker-Enfants malades hospital, to assess the safety and efficacy of therapy by transplantation of autologous HSCs modified with the DREPAGLOBE vector. The teams examined factors that may influence the uptake of genetically modified cells in sickle cell patients, and the efficacy of transplantation in this devastating disease.

The primary endpoint of the clinical trial was short-term safety, and the secondary endpoints were long-term efficacy and safety. After 18 to 36 months of follow-up, no treatment-related adverse events or signs of abnormal hematopoiesis were observed. However, despite a similar number of vector copies in the initial treatment, the frequency of “corrected” red blood cells and disease correction varied from patient to patient. Cellular analysis in patients with poor graft intake showed that these differences can almost certainly be explained by the host's degree of inflammation and its repercussions on the functionality of their HSCs. The researchers have thus characterized three criteria that must be met for gene therapy to be effective: the number of corrected and grafted HSCs, the level of inflammation and an absence of skewing in HSC differentiation. Thanks to these elements, a specific treatment will be proposed to patients in the new clinical trial currently in preparation (DREPAMIR trial).

The results of this trial, recently published in the prestigious scientific journal Nature Communications, confirm that this gene therapy based on DREPAGLOBE is safe and free of side effects in both the short and long term. However, its efficacy is variable and depends on the number of transplanted HSCs and their inflammatory state, assessed by gene activity, in relation to the host's biological characteristics. Although the response to treatment remains to be improved for certain patients, this study represents a major step forward in obtaining a safe and effective gene therapy to treat sickle cell disease, in a personalized manner and with proven long-term benefits.

Reference :
Severe inflammation and lineage skewing are associated with poor engraftment of engineered hematopoietic stem cells in patients with sickle cell disease
S Sobrino et al., Nat Commun., 2025
Corresponding author : Marina Cavazzana
DOI : 10.1038/s41467-025-58321-4