Final Report Summary - REGENERATIVETHERAPY (Cell and gene therapy approaches for inherited diseases with unsatisfying or no therapeutic option)
Personalized medicine, considered as the medicine of tomorrow, suggests treating patients with the necessary and appropriate tools specific for each pathology. In the case of primary immunodeficiencies, personalized medicine can replace cells carrying the genetic mutation by healthy cells. This replacement, known as allogeneic transplantation, is done by transplanting stem cells harvested from the iliac crest from genetically compatible and healthy donors. However, if this compatible donor is not available, several obstacles such as graft rejection, graft-versus-host disease and infection burden the use of a partially compatible transplant. The innovative therapeutic alternative that has proved its success is gene therapy. One of the major advantages of gene therapy is that it uses the stem cells of the patient thus abolishing the immunological problems. A modified but not replicative virus called vector able to express the healthy gene genetically modifies patients stem cells. In order to be able to graft these cells to the patient and maximize their therapeutic potential, the patient receives a limited cycle of chemotherapy treatment without immunosuppression. The project that was funded by the European Research Council (ERC) allowed to treat by gene therapy patients affected with Wiskott-Aldrich and X-linked Severe Combined Immunodeficiency.
Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency linked to the X chromosome and associated with microthrombocytopenia. The work carried during the ERC project showed that a single injection of genetically modified haematopoietic stem cells, through the use of a lentiviral vector expressing the healthy gene and thus giving a functional protein, significantly reduces the symptoms and duration of hospitalization linked to the disease, and restores an immune system close to the normal state (Hacein-Bey Abina S et al., JAMA, 2015). Patients can therefore return to school full-time and stop the medication they need. Only the platelets counts do not reach a normal levels but their counts was sufficiently improved to stop the major bleeding symptoms.
The severe X-linked combined immune deficiency (SCID-X1), a disease characterized by the absence of T cells and NK cells, with a life expectancy limited to one year in the absence of treatment, is characterized by a mutation of an essential component of the hematopoietic cytokine receptor. Gene therapy for SCID-X1 consists on the transplantation of hematopoietic stem cells expressing the healthy gene into the patient. This clinical trial based on the use of a self-inactivated γ-retrovirus vector that has been conducted at the Necker-Children Hospital, Paris France, has successfully treated four patients without a compatible donor (Hacein-Bey Abina S et al., N Engl J Med, 2014). This clinical trial has been conducted as well in two other sites, Boston (principal investigator: Sung-Yun Pai) and London (principal investigator: Adrian Thrasher) with overlapping clinical and biological results.
For patients with immunodeficiencies for whom gene therapy is not available or adult patients with leukemia, partially compatible allogenic HSCT that constitutes the only curative treatment, is accompanied by a slow immune reconstitution and thus high rates of infections. In an attempt to speed up immune reconstitution, we have set up a new culture system based on the use of a chimeric protein that enables the in vitro generation of large amounts of T progenitor cells with a high T-lymphopoietic potential in vitro and in vivo (xenogenic transplantation model). Importantly, T cells are undetectable by flow cytometry after the protein exposure rendering the risk of inducing an allogenic reaction and thus GVHD unlikely. This system will be used in patients in 2017 or early 2018 through a phase I/II clinical trial.
Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency linked to the X chromosome and associated with microthrombocytopenia. The work carried during the ERC project showed that a single injection of genetically modified haematopoietic stem cells, through the use of a lentiviral vector expressing the healthy gene and thus giving a functional protein, significantly reduces the symptoms and duration of hospitalization linked to the disease, and restores an immune system close to the normal state (Hacein-Bey Abina S et al., JAMA, 2015). Patients can therefore return to school full-time and stop the medication they need. Only the platelets counts do not reach a normal levels but their counts was sufficiently improved to stop the major bleeding symptoms.
The severe X-linked combined immune deficiency (SCID-X1), a disease characterized by the absence of T cells and NK cells, with a life expectancy limited to one year in the absence of treatment, is characterized by a mutation of an essential component of the hematopoietic cytokine receptor. Gene therapy for SCID-X1 consists on the transplantation of hematopoietic stem cells expressing the healthy gene into the patient. This clinical trial based on the use of a self-inactivated γ-retrovirus vector that has been conducted at the Necker-Children Hospital, Paris France, has successfully treated four patients without a compatible donor (Hacein-Bey Abina S et al., N Engl J Med, 2014). This clinical trial has been conducted as well in two other sites, Boston (principal investigator: Sung-Yun Pai) and London (principal investigator: Adrian Thrasher) with overlapping clinical and biological results.
For patients with immunodeficiencies for whom gene therapy is not available or adult patients with leukemia, partially compatible allogenic HSCT that constitutes the only curative treatment, is accompanied by a slow immune reconstitution and thus high rates of infections. In an attempt to speed up immune reconstitution, we have set up a new culture system based on the use of a chimeric protein that enables the in vitro generation of large amounts of T progenitor cells with a high T-lymphopoietic potential in vitro and in vivo (xenogenic transplantation model). Importantly, T cells are undetectable by flow cytometry after the protein exposure rendering the risk of inducing an allogenic reaction and thus GVHD unlikely. This system will be used in patients in 2017 or early 2018 through a phase I/II clinical trial.