Study of gene therapy treatment in Wiskott-Aldrich syndrome

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Teams from the AP-HP, University of Paris, Inserm, within the Imagine Institute, the University College of London, and Généthon, have carried out work on treatment by gene therapy consisting of transplanting the patient’s own genetically modified hematopoietic stem cells as part of a phase I/II clinical trial, promoted by Genethon, in 8 patients with Wiskott-Aldrich syndrome (WAS). The results of this work, carried out in parallel at the Hôpital Necker-Enfants Malades AP-HP, at the Great Ormond Street Hospital and at the Royal Free Hospital in London and coordinated by Pr Marina Cavazzana, Pr Adrian Thrasher and Pr Emma Moris , were published January 24, 2022 in Nature Medicine.

Wiskott-Aldrich syndrome (WAS) is an X-linked complex immune deficiency caused by mutations in the WAS gene which codes for the WAS protein (WASp). This protein is key in the regulation of cytoskeletal actin 1 in hematopoietic cells.

Deficiency of this protein is responsible for small platelet 2 thrombocytopenia and poor function of white blood cells, especially T, B, natural killer and dendritic cells.

The more severe clinical phenotype is characterized by severe infections, bleeding, eczema and manifestations of autoimmunity with a significant risk of developing tumor complications. The severity of clinical expression is related to the level of WAS protein expression. Without curative treatment, patients do not survive beyond the second-third decade of life.

The treatment of choice consists of allogeneic transplantation 3 of HLA-geno-identical hematopoietic stem cells, which has very good results, especially if it is carried out early (<5 years).

The prognosis of the allogeneic transplant actually depends on a number of parameters in addition to the patient’s age, including the degree of HLA compatibility between donor and recipient and the level of hematopoietic uptake.

In the absence of an HLA-compatible donor, the research teams have proposed a treatment by gene therapy which consists of taking blood stem cells carrying the genetic anomaly from patients (CD34+ hematopoietic stem cells), then correct in the laboratory by introducing the healthy WAS gene using a lentiviral vector developed by Anne Galy’s team at Généthon, where the clinical batches of vectors were also produced. The corrected cells are then injected into the patients, previously treated with chemotherapy in order to eliminate the diseased cells and make room for the autologous cells corrected in vitro which will then give rise to the various cells that make up the blood (white and red blood cells, platelets).

In the article which has just been published , the long-term clinical and biological results (median follow-up of 7.6 years) of the phase I/II trial in 8 patients with WAS are described with a special attention paid to two serious complications of this disease: thrombocytopenia and autoimmunity. It should be emphasized that all the patients included in this trial had the more severe form of this immune deficiency and were not eligible for an allogeneic bone marrow transplant.

After gene therapy, the genetically corrected hematopoietic cells showed stabilized engraftment, thus confirming the first results reported in JAMA a few years ago for 6 of them.

The stability of the grafted genetically modified stem cells has made it possible to correct the main symptoms of the disease such as recurrent severe infections or eczema and has made it possible to improve or resolve bleeding and signs of autoimmunity. T cell function was completely restored as demonstrated by the total number of naïve T cells, the restoration of the immunological synapse as well as the functions of these cells which are essential to fight infections.

No adverse effect linked to the use of a retroviral vector has been reported, nor has there been any lack of stability of the graft of genetically modified cells.

Analysis of lentiviral integration sites reveals a polyclonal profile without any clonal expansion or dangerous integration of the vector (risk of neoplastic transformation). Indeed, thanks to lentiviral vectors, the new genetic information is introduced in a stable and random way into the patient’s genome. The ability to sequence the entire genome makes it possible to follow exactly the sites of integration of the new genetic material and to ensure their harmlessness with regard to the physiological functions of the target cell. This sequencing made it possible to validate the long-term safety of these retroviral vectors because no genetic disturbance was observed.

Note: a 30-year-old patient was treated in this trial, thus showing the effectiveness of this treatment in adult patients with a thymus that could be thought to be little or not functional after long years of illness. Similarly, a complete correction of the B lymphocyte compartment was obtained, which made it possible to stop the immunoglobulin substitution in 5 treated patients and to see a significant reduction or even disappearance of the signs of autoimmunity.

All treated patients saw their episodes of spontaneous bleeding decrease significantly in frequency and severity, although for 5 patients the number of platelets remained below normal values.

All in all, gene therapy by gene addition confirms its therapeutic interest for a complex deficit of cellular immunity such as Wiskott Aldrich syndrome. New studies are underway to try to continue to optimize these long-term clinical results.

1 This is a protein in the cell membrane whose contraction and relaxation activity allows each blood cell to do its job well, such as moving from place to place or eliminating a "diseased” cell. in the case of killer cells.

2 This is the pathological decrease in the number of platelets which, in addition, have a reduced size compared to the physiological value.

3 The term allogeneic refers to cells, tissues or organs taken from a healthy donor to be transplanted into a recipient who is strongly, but not entirely, genetically compatible with the donor.


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