Gene therapy: Therapeutic gene causing lymphoma

  title={Gene therapy: Therapeutic gene causing lymphoma},
  author={Niels-Bjarne Woods and Virginie Bottero and Manfred Schmidt and Christof von Kalle and Inder M. Verma},
The development of T-cell leukaemia following the otherwise successful treatment of three patients with X-linked severe combined immune deficiency (X-SCID) in gene-therapy trials using haematopoietic stem cells has led to a re-evaluation of this approach. Using a mouse model for gene therapy of X-SCID, we find 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. Gene-therapy trials for X-SCID… 

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

Assessing the risk of T-cell malignancies in mouse models of SCID-X1.

  • B. Sorrentino
  • Biology, Medicine
    Molecular therapy : the journal of the American Society of Gene Therapy
  • 2010
Most of the more than 30 treated patients have had full reconstitution of T-cell–mediated immunity, with restoration of B-cell function in fewer, but significant numbers of, cases, however, in both SCID-X1 trials, some patients developed T- cell malignancies that were clearly related to insertional mutagenesis from the integrated vector.

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.

Gene therapy for primary immunodeficiencies.

  • A. Thrasher
  • Biology, Medicine
    Immunology and allergy clinics of North America
  • 2008

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.

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.

Combating oncogene activation associated with retrovirus-mediated gene therapy of X-linked severe combined immunodeficiency

The current understanding of the mechanism behind this leukemogenesis involves three critical and cooperating factors, i.e., viral integration, oncogene activation, and the function of the therapeutic gene.

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.

Combating oncogene activation associated with retrovirus-mediated gene therapy of X-linked severe combined immunodeficiency.

  • B. StraussE. Costanzi-Strauss
  • Biology, Medicine
    Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
  • 2007
The current understanding of the mechanism behind this leukemogenesis involves three critical and cooperating factors, i.e., viral integration, oncogene activation, and the function of the therapeutic gene.

Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity

Current information on the mechanisms of insertional mutagenesis in hematopoietic stem and progenitor cells due to integrating gene transfer vectors are summarized, and newlydeveloped approaches for minimizing genotoxicity are introduced as a way to further move HSC gene therapy forward into broader clinical application.



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

Ex vivo gene therapy with gamma(c) can safely correct the immune deficiency of patients with X-linked severe combined immunodeficiency and allow patients to have a normal life.

Restoration of lymphoid populations in a murine model of X-linked severe combined immunodeficiency by a gene-therapy approach.

Transfer of the human gamma(c) gene to repopulating hematopoietic stem cells using an ecotropic retrovirus resulted in an increase in T cells, B cells, natural killer cells, and intestinal intraepithelial lymphocytes, as well as normalization of the CD4:CD8 T-cell ratio and of serum Ig levels.

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.

Lack of dominant-negative effects of a truncated gamma(c) on retroviral-mediated gene correction of immunodeficient mice.

Data indicate that residual expression of the endogenous truncated gamma(c) did not lead to dominant-negative effects in this murine model and suggest that patient selection may not be strictly necessary for gene therapy of XSCID.

In vivo competitive studies between normal and common gamma chain-defective bone marrow cells: implications for gene therapy.

It is extrapolate that genetic correction of XSCID HSCs will result in selective advantage of gene-corrected lymphoid lineages with consequent restoration of lymphocyte populations and high probability of clinical benefit.

The oncogenic LIM protein Rbtn2 causes thymic developmental aberrations that precede malignancy in transgenic mice.

The data provide a biological explanation for the role of RBTN2 in tumorigenesis and presumably RBTN2 expression in T cells after the translocation t(11;14) in children has the same effect.

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.

Lentivirus Vector-Mediated Hematopoietic Stem Cell Gene Transfer of Common Gamma-Chain Cytokine Receptor in Rhesus Macaques

The efficiency of marking, gene expression, and transplant of bone marrow and peripheral blood CD34+ cells using a self-inactivating lentivirus vector bearing an internal murine leukemia virus long terminal repeat derived from a murine retrovirus adapted to replicate in rhesus macaques is tested.

Retroviral marking of canine bone marrow: long-term, high-level expression of human interleukin-2 receptor common gamma chain in canine lymphocytes.

The long-term expression of human gammac in a high proportion of normal canine lymphocytes predicts that retrovirus-mediated gene correction of hematopoietic cells may prove to be of clinical benefit in humans affected with this XSCID.

Comparison of five retrovirus vectors containing the human IL-2 receptor gamma chain gene for their ability to restore T and B lymphocytes in the X-linked severe combined immunodeficiency mouse model.

It is concluded that the MFG-S-hIL2RG vector provides the best opportunity for in vivo selection and development of B and T lymphocytes for human XSCID gene therapy.