Gene therapy: X-SCID transgene leukaemogenicity

  title={Gene therapy: X-SCID transgene leukaemogenicity},
  author={Adrian J. Thrasher and H Bobby Gaspar and Christopher Baum and Ute Modlich and Axel Schambach and Fabio Candotti and Makoto Otsu and Brian P. Sorrentino and Linda Scobie and Ewan R Cameron and Karen Blyth and Jim Neil and Salima Hacein-Bey Abina and Marina Cavazzana‐Calvo and Alain Fischer},
Arising from: Woods, N.-B., Bottero, V., Schmidt, M., von Kalle, C. & Verma, I. M. 440, 1123 (2006); see also communication from Pike-Overzet et al.; Woods et al. replyGene therapy has been remarkably effective for the immunological reconstitution of patients with severe combined immune deficiency, but the occurrence of leukaemia in a few patients has stimulated debate about the safety of the procedure and the mechanisms of leukaemogenesis. Woods et al. forced high expression of the corrective… 

[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 for SCID

This work reports that SCID-X1 and adenosine deaminase SCID have been successfully treated with hematopoietic stem cell gene therapy (HSC-GT) and patients show impressive levels of immune reconstitution.

Safer vectors for gene therapy of primary immunodeficiencies.

Existing methodologies for PID GT are summarized highlighting the importance of animal models in the PID GT success and focusing on new gene transfer vectors to achieve safe, efficient and stable gene modification.

Gene therapy: Is IL2RG oncogenic in T-cell development?: X-SCID transgene leukaemogenicity (reply)

Using a lentiviral vector and a murine model of X-linked severe combined immune deficiency (X-SCID), we have shown that mice transplanted with cells constitutively overexpressing the therapeutic gene

Sola dosis facit venenum. Leukemia in gene therapy trials: a question of vectors, inserts and dosage?

The mechanisms of insertional mutagenesis, the fuction of the Il2RG gene and the future developments in the field are reviewed and the unfortunate side effects of gene therapy have given more insight into the development of human T-ALL.

New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy.

This review discusses the various forms of SCID in relation to normal T-cell development and considers the possible role of LMO2 and other T-ALL oncogenes in the development of adverse effects as seen in the X-linked SCID gene therapy trial.

Perspectives on stem cell gene therapy for genetic disorders

Researchers should continue to aim for further improvement of HSC gene therapy to maximize both safety and efficacy, and a new model system possibly constituting such an ideal platform has come to reality; that is, patient‐/disease‐specific induced pluripotent stem cells (iPSCs).

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.

A Novel Model of SCID-X1 Reconstitution Reveals Predisposition to Retrovirus-induced Lymphoma but No Evidence of γC Gene Oncogenicity.

It is concluded that the SCID-X1 phenotype can be corrected safely by stable ectopic expression of γC and that the transgene is not significantly oncogenic when expressed in this context, however, an underlying predisposition conferred by the SCIDsX1 background appears to collaborate with insertional mutagenesis to increase the risk of tumor development.

A novel model of SCID-X1 reconstitution reveals predisposition to retrovirus-induced lymphoma but no evidence of gammaC gene oncogenicity.

It is concluded that the SCID-X1 phenotype can be corrected safely by stable ectopic expression of gammaC and that the transgene is not significantly oncogenic when expressed in this context, however, an underlying predisposition conferred by theSCID- X1 background appears to collaborate with insertional mutagenesis to increase the risk of tumor development.



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.

Gene therapy: Therapeutic gene causing lymphoma

Using a mouse model for gene therapy of X-SCID, it is found that the corrective therapeutic gene IL2RG itself can act as a contributor to the genesis of T-cell lymphomas, with one-third of animals being affected.

LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1

Retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.

Lymphoid development and function in X-linked severe combined immunodeficiency mice after stem cell gene therapy.

Results show that retroviral-mediated gene transfer can improve murine XSCID and suggest that similar strategies may prove beneficial in human clinical trials.

Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative Conditioning

Sustained engraftment of engineered HSCs with differentiation into multiple lineages resulted in increased lymphocyte counts, improved immune functions, and lower toxic metabolites, indicating the safety and efficacy of HSC gene therapy combined with nonmyeloablative conditioning for the treatment of SCID.

Leukemias following retroviral transfer of multidrug resistance 1 (MDR1) are driven by combinatorial insertional mutagenesis.

It is shown that leukemias associated with retroviral expression of MDR1 depend on high vector dose, and involve the selection of clones with combinatorial insertional mutagenesis of proto-oncogenes or other signaling genes, and that insertional mutants can be amplified in vitro before transplantation.

A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency.

The sustained correction of X-linked severe combined immunodeficiency disease by ex vivo, retrovirally mediated transfer of the γc gene into CD34+ cells in four of five patients with the disease has been reported.

Stable and functional lymphoid reconstitution of common cytokine receptor gamma chain deficient mice by retroviral-mediated gene transfer.

That Gamma(c) gene transfer to hematopoietic precursor cells can correct the immune system abnormalities in gamma(c)(-) mice supports the feasibility of in vivo retroviral gene transfer as a treatment for human SCIDX1.

Gene Therapy Insertional Mutagenesis Insights

In a milestone study describing the first “cure” of a genetic disease by retroviral gene therapy, 9 out of 10 infants born with X-linked severe combined immunodeficiency were successfully treated with autologous bone marrow stem cells infected with Tournaisian stem cells.