Therapeutic gene causing lymphoma

Posted by & filed under Part 02: PERSPECTIVES, Part 20: IMMUNE AND DEFENSE SYSTEMS.

Nature. 2006 Apr 27;440(7088):1123.
Gene therapy: therapeutic gene causing lymphoma.
Woods NB, Bottero V, Schmidt M, von Kalle C, Verma IM.

3 children who underwent gene therapy for X-linked Severe Combined Immunodeficiency (X-SCID),using therapeutic administration of the IL2RG gene, developped T-cell leukaemia.
In this article, the investigators conducted long term studies in a murine moodel of X-SCID using a similar treatment. One third of the mice developped T-cell lymphomas. This implicates IL2RG in the lymphomagenesis in this model. It underscores the requirement for long-term studies in animals before conducting human gene therapy trials.

For more information on the treatement of genetic disease and on X-SCID, see chapters 5 and 185 of OMMBID, respectively.
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Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator

2 Responses to “Therapeutic gene causing lymphoma”

  1. pcampeau

    From Chapter 5

    Chapter 5: Treatment of Genetic Disease
    Authors: Eileen P. Treacy, David Valle, Charles R. Scriver

    Somatic Gene Therapy

    Our views about the role of somatic gene therapy and the mechanisms for its implementation have evolved in recent years.112-116 The range of disorders that might be considered amenable to this type of therapy has expanded from single-gene disorders to include cancer, AIDS, other infectious diseases, and atherosclerosis; in addition, recombinant protein therapies (e.g., with insulin, erythropoietin, or clotting factor) could be converted to in vivo production via somatic gene therapy. During the past 10 years, more than 300 clinical protocols and over 3000 patients have experienced somatic gene therapy (see references for gene therapy trial in progress at Wiley:; the experience with the genetic diseases discussed here is far less.

    There are three approaches to somatic cell gene therapy:113,117 (1) ex vivo, where cells are removed from the body and incubated with a vector, and the gene-engineered cells are then returned to the body; (2) in situ, where the vector is placed directly into the affected tissues; and (3) in vivo, where a vector would be injected directly into the bloodstream. Figure 5-6 describes the in vivo and in vitro strategies.

    The repertoire of delivery systems, which began with retroviral vectors, has expanded to include vectors based on adenovirus, adeno-associated virus, herpes virus, vaccinia, and other agents, and nonviral systems such as liposomes, DNA-protein conjugates, and DNA-protein-defective virus conjugates. Emphasis has shifted from ex vivo modification of cells to in vivo delivery, although the pursuit continues in the attempt to achieve ex vivo manipulation of bone marrow cells, tumor cells, and cultured fibroblasts and epithelium.

    Retroviral vectors efficiently integrate at random sites in the genome of dividing cells, permanently altering the recipient. Typically one or a few integrated copies of the recombinant vectors are found in each transduced cell. Currently, about 60 percent of approved clinical protocols for somatic gene therapy use retroviral vectors (see Despite this, retroviral vectors have several disadvantages: first, they require dividing cells as a target; second, they are difficult to produce at titers high enough for most in vivo approaches; and, third, depending on its location, retroviral integration may adversely alter the expression of a gene in the area (e.g., a proto-oncogene) and produce a transformed cellular phenotype. Adenovirus vectors, in contrast, offer a high titer and a better ability to infect large numbers of cells in vivo, but there is concern about toxic effects on infected cells, and the therapeutic effect is transient, with expression for only days or weeks. Recent results with newer adenoviral vectors, in which nearly all adenoviral sequences have been removed, show promise for reduced toxicity and much longer expression (several months).118,119 Vectors based on adeno-associated virus have the potential to provide high titer, safety, and long-term expression. Recent reports using adeno-associated viral vectors introduced into liver and skeletal muscle have shown long-term high-level expression.120 It is believed that the recombinant virus persists as an episome in these cells, reducing the risk of malignant transformation. Vaccinia vectors and nonviral systems provide only transient expression, since they do not provide for DNA integration. Transient expression may be perfectly acceptable for some applications, such as eliciting an altered immune response to malignant cells or treatment of an acute disease process. There is need for new delivery systems or vectors that can be delivered efficiently in vivo (preferably by intravenous injection), can be targeted to specific cell types, can alter resting or dividing cells, and will persist indefinitely, whether by integration into the chromosome or by an extrachromosomal (episomal) mechanism.

    Recent studies with lentiviral vectors are also promising in these regards.121,122 DNA vectors may also be delivered directly without the aid of viruses by using pharmaceutical methods to target DNA vectors to specific cells and the nucleus. The approaches include the use of purified DNA via intramuscular injection (naked DNA, particles coated with DNA, cationic lipids, or other ligands) to target DNA to cell types and enhance their activity.

  2. pcampeau

    Excerpts from chapter 185

    Chapter 185: T Cell and Combined Immunodeficiency Disorders
    Authors: John W. Belmont, Jennifer M. Puck


    Prenatal diagnosis of SCID is best performed by specific mutation diagnosis of amniocyte or chorionic villus DNA if the genotype of a proband in the family is known.586 When the genotype of a deceased proband is unknown, but the phenotype is well documented, fetal blood sampling has been successfully used in at-risk pregnancies. Low numbers of T cells and defective T cell blastogenic responses to mitogens can be definitively demonstrated in affected fetuses by week 17 of gestation.587

    In one study of utilization of prenatal diagnosis for X-linked SCID, 93 percent of families at risk for having an affected pregnancy desired prenatal testing, whether or not termination of pregnancy was a consideration.586 In only 2 instances of 13 affected male predictions, did parents choose pregnancy termination. Other families’ prepared for optimal treatment of an affected newborn including selection of a BMT center, HLA testing of family members, and initiating a search for a matched unrelated donor for bone marrow. One family chose an experimental in utero BMT.586

    The best current treatment for SCID is HLA-matched BMT.589-593 Unfortunately, most patients lack a matched, related donor. Haploidentical, T-cell-depleted BMT has been quite successful.593 Matched unrelated donor transplantation of marrow or cord blood stem cells has also been used. Infants transplanted immediately after birth are less likely to have serious pretransplant infections or failure to thrive. They also have more rapid engraftment, fewer posttransplant infections, and less graft versus host disease than those whose BMT is delayed.593 Nevertheless, some posttransplant patients have graft versus host disease; many fail to make adequate antibodies and require long-term immunoglobulin replacement; and some develop autoimmune phenomena due to lymphocyte dysregulation. The oldest surviving individuals with SCID received HLA matched related BMT and are now in their twenties and in excellent health. As larger numbers of children are now growing up after BMT for SCID, study of very-long-term outcomes is possible.

    The concept of prenatal treatment for XSCID has reemerged after initial low rates of success.582,588 In two instances, fetuses affected with XSCID were infused intraperitoneally between 17 and 20 weeks of gestation with paternal, T-cell-depleted, or CD34+-enriched paternal bone marrow cells. Infants were born with engrafted, functional T cells from their donors.

    XSCID and JAK3 SCID also are promising candidate diseases for gene transfer therapy for several reasons. The success of BMT indicates that stem-cell correction should reverse the phenotype. Ubiquitous hematopoietic cell expression suggests that use of strong promotors in retroviral constructs may not be harmful. A natural in vivo selective advantage exists for lymphocytes expressing functional γc or JAK3, as illustrated by female carrier lymphocytes showing nonrandom X chromosome inactivation in XSCID and a natural reversion of a SCID-causing IL2RG mutation in T cells of one patient.594 Retroviral correction of the defects in human cell lines596,597 and mouse knockout models598 has been successful. The major limitation of retroviral gene therapy in humans has been the poor efficiency of gene transduction into self-renewing bone marrow hematopoietic stem cell populations. Nonetheless, a preliminary report from Cavazzana-Calvo et al. indicates development of functional T cells in two infants with XSCID after retroviral transduction of their CD34+ bone marrow cells with a γc retrovirus.599 Further new approaches offer considerable promise; for example, cytokine administration prior to stem-cell harvest has been shown to amplify the available stem cell pool for transduction by retroviruses.600

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