Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.

  title={Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.},
  author={Salima Hacein-Bey-Abina and Françoise Le Deist and Fr{\'e}d{\'e}rique Carlier and C{\'e}cile Bouneaud and Christophe Hue and Jean-Pierre de Villartay and Adrian J. Thrasher and Nico M. Wulffraat and Ricardo U. Sorensen and Sophie Dupuis-Girod and Alain Fischer and E. Graham Davies and Wietse Kuis and Lilly Leiva and Marina Cavazzana‐Calvo},
  journal={The New England journal of medicine},
  volume={346 16},
BACKGROUND X-linked severe combined immunodeficiency due to a mutation in the gene encoding the common gamma (gamma(c)) chain is a lethal condition that can be cured by allogeneic stem-cell transplantation. We investigated whether infusion of autologous hematopoietic stem cells that had been transduced in vitro with the gamma(c) gene can restore the immune system in patients with severe combined immunodeficiency. METHODS CD34+ bone marrow cells from five boys with X-linked severe combined… 

Gene Therapy of X-Linked Severe Combined Immunodeficiency

A successful gene therapy demonstrates that in a setting where transgene expression provides a selective advantage, a clinical benefit can be expected and is used as a basis for a clinical trial of the SCID-X1 disorder caused by common γ (γc) gene mutations.

Correction of canine X-linked severe combined immunodeficiency by in vivo retroviral gene therapy.

This is the first demonstration that in vivo gene therapy targeting HSCs can restore both cellular and humoral immunity in a large-animal model of a fatal immunodeficiency, and achievement of durable immune reconstitution in XSCID dogs is demonstrated.

Efficacy of gene therapy for X-linked severe combined immunodeficiency.

After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1 and may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable.

Gene therapy studies in a canine model of X-linked severe combined immunodeficiency.

Gen therapy studies performed in a canine model of XSCID demonstrate that durable T cell reconstitution and thymopoiesis with no evidence of any serious adverse events and sustained marking in myeloid cells and B cells can be achieved for up to 5 years without any pretreatment conditioning.

Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease

This review provides an overview about the different gene therapy approaches used over the last 20 years to treat SCID-X1 patients, particularly focusing on lymphoid immune reconstitution, as well as the developments that have improved the process and outcomes.

Gene Therapy Studies in a Canine Model of X-Linked Severe Combined Immunodeficiency

These studies demonstrate that durable T cell reconstitution and thymopoiesis with no evidence of any serious adverse events and, in contrast to the human XSCID patients, sustained marking in myeloid cells and B cells with Reconstitution of normal humoral immune function can be achieved for up to 5 years without any pretreatment conditioning.

Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?

The clinical experience of gene therapy for SCID-X1 is put into perspective, with the development and implementation of new generations of safer vectors such as self-inactivating gammaretroviral or lentiviral vectors as well as major advances in integrome knowledge.

[Gene therapy of SCID-X1].

Activation of cellular proto-oncogenes by accidental integration of the gene vector has been identified as the underlying mechanism and improved vector technology in combination with other protocol modifications may reduce the risk of this side effect.



Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease.

A gene therapy trial for SCID-X1 was initiated, based on the use of complementary DNA containing a defective gammac Moloney retrovirus-derived vector and ex vivo infection of CD34+ cells, which provided full correction of disease phenotype and clinical benefit.

Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.

The vestigial thymus in infants with severe combined immunodeficiency is functional and can produce enough T cells after bone marrow transplantation to provide normal immune function.

Intrinsic defects of B cell function in X‐linked severe combined immunodeficiency

Although hematopoietic stem cell transplantation restores a diverse repertoire of class‐switched B cell clones, on further analysis these are almost all of donor origin, this suggests that host B cells, which predominate after unconditioned transplantation, are still defective even in the presence of normal T cells.

Restoration of lymphocyte function in Janus Kinase 3-deficient mice by retroviral-mediated gene transfer

Results show that gene replacement is a feasible treatment strategy for this disease and that naturally occurring in vivo selection of corrected cells is an important advantage of this approach.

Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.

Transplantation of marrow from a related donor is a life-saving and life-sustaining treatment for patients with any type of severe combined immunodeficiency, even when there is no HLA-identical donor.

Defective IL7R expression in T-B+NK + severe combined immunodeficiency

It is demonstrated that defective IL7R expression causes T–B +NK+ SCID, indicating that the T- cell, but not the NK-cell, defect in XSCID results from inactivation of IL-7Rα signalling.

Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer

It is concluded that replication-competent viruses arising from producer cells making Retroviral vectors can be pathogenic in primates, which underscores the importance of carefully screening retroviral producer clones used in human trials to exclude contamination with replication- competent virus.

Long-term chimerism and B-cell function after bone marrow transplantation in patients with severe combined immunodeficiency with B cells: A single-center study of 22 patients.

The results strongly suggest that, in some transplanted patients, host B cells can cooperate with donor T cells to fully mature in Ig-producing cells.

Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients.

Results of this retrospective analysis should lead to new protocols adapted to SCID disease, considering that disease-related as well as BMT-related parameters influence the development of immune function and thereby long-term outcome after HLA-nonidentical T-cell-depleted BMT.

A primary T-cell immunodeficiency associated with defective transmembrane calcium influx.

This primary T-cell immunodeficiency appears to be due to defective Ca2+ entry through the plasma membrane, which did not alter B-cell proliferation, platelet function, and polymorphonuclear neutrophil (PMN) function.