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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current experience with gene therapy for X-linked severe combined immunodeficiency disorder (X-SCID) suggests that we might now be at the point where it can be considered the 'standard of care'. This therapy carries an unquantified risk of leukaemia, raising important questions for regulators. How dangerous does a potentially curative therapy for a fatal illness need to be before we call it unsafe. How uncertain does a risk need to be for us to regard a therapy as still 'experimental'? Whose interests should prevail? Here I argue that in X-SCID it is the parents and children whom we should listen to first and foremost. How far does this patient-centred approach to licensing therapies extend? Can it be given a rational basis?
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PMID:Gene therapy in the clinic: whose risks? 1549 99

Recent reports linking insertional activation of LMO2 following gene therapy for X-linked severe combined immunodeficiency (X-SCID) have led to a re-evaluation of risks following gene therapy with retroviral vectors. In our analysis of 702 integration sites in rhesus macaques that underwent transplantation up to 7 years earlier with autologous CD34+ cells transduced with amphotropic murine leukemia virus (MLV)-derived retroviral vectors containing marker genes, we detected insertion into one locus, the Mds1/Evi1 region, a total of 14 times in 9 animals. Mds1/Evi1 integrations were observed stably long term, primarily in myeloid cells. We hypothesize that this over-representation likely results from an impact on the self-renewal and engraftment potential of CD34+ progenitor cells via insertional mutagenesis at this specific locus. There is no evidence of ongoing in vivo clonal expansion of the Mds1/Evi1 populations, and all animals are hematologically normal without evidence for leukemia. Characterization of integration sites in this relevant preclinical model provides critical information for gene therapy risk assessment as well as identification of genes controlling hematopoiesis.
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PMID:Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells. 1593 56

The experience of the past 3 years, since the first case of leukemia was reported in a child cured of X-linked severe combined immunodeficiency (X-SCID) by gene therapy, indicates that the potential genotoxicity of retroviral integration in hematopoietic cells will remain a consideration in evaluating the relative risks versus benefits of gene therapy for specific blood disorders. Although many unique variables may have contributed to an increased risk in X-SCID patients, clonal dominance or frank neoplasia in animal models, clonal dominance in humans with chronic granulomatous disease, and the ability of retroviral integration to immortalize normal bone marrow cells or convert factor-dependent cells to factor independence suggest that transduction of cells with an integrating retrovirus has the potential for altering their subsequent biologic behavior. The selective pressure imposed during in vitro culture or after engraftment may uncover a growth or survival advantage for cells in which an integration event has affected gene expression. Such cells then carry the risk that subsequent mutations may lead to neoplastic evolution of individual clones. Balancing that risk is that the vast majority of integration events seem to be neutral and that optimizing vector design may diminish the probability of altering gene expression by an integrated vector genome. Several cell culture systems and animal models designed to empirically evaluate the safety of vector systems are being developed and should provide useful data for weighing the relative risks and benefits for specific diseases and patient populations. Gene therapy interventions continue to have enormous potential for the treatment of disorders of the hematopoietic system. The future of such efforts seems bright as we continue to evolve and improve various strategies to make such interventions both effective and as safe as possible.
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PMID:Genotoxicity of retroviral integration in hematopoietic cells. 1662 21

A successful gene therapy clinical trial that also encountered serious adverse effects has sparked extensive study and debate about the future directions for retrovirus-mediated interventions. Treatment of X-linked severe combined immunodeficiency with an oncoretrovirus harboring a normal copy of the gammac gene was applied in two clinical trials, essentially curing 13 of 16 infants, restoring a normal immune system without the need for additional immune-related therapies. Approximately 3 years after their gene therapy, tragically, 3 of these children, all from the same trial, developed leukemia as a result of this experimental treatment. 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. In this review, we will explore the causes of this unwanted event and some of the possibilities for reducing the risk of its reoccurrence.
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PMID:Combating oncogene activation associated with retrovirus-mediated gene therapy of X-linked severe combined immunodeficiency. 1746 21

Patients with chronic granulomatous disease (CGD) cannot generate reactive oxygen metabolites, and suffer from severe recurrent infections and dysregulated inflammation. Haematopoietic stem cell transplantation is the only established option for definitive cure for patients with a suitable donor and is indicated when conventional prophylaxis and therapy with antimicrobial medication fail. Gene therapy has the potential to cure CGD, and several clinical trials have been conducted since 1997. Whereas initial studies resulted in low and short-term engraftment of CGD-corrected cells, recent trials demonstrated clinical benefit when engraftment was enhanced by busulfan conditioning prior to infusion of gene-corrected cells. However, the progress in gene therapy has been hampered by the appearance of insertional mutagenesis causing leukaemia in a trial for patients with X-linked severe combined immunodeficiency and by the emergence of dominant clones in a recent trial for the X-linked form of CGD. These findings stimulated the development of modified vector systems that demonstrate reduced genotoxicity in vitro and in animal models. New gene therapy protocols that allow efficient gene transfer and durable expression but limit the risk for insertional mutagenesis are envisioned to become an important therapeutic option for patients with CGD.
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PMID:Gene therapy for chronic granulomatous disease. 1803 46

X-linked severe combined immunodeficiency (SCID-X1) is an inherited disease caused by inactivating mutations in the gene encoding the interleukin 2 receptor common gamma chain (IL2RG), which is located on the X-chromosome. Affected boys fail to develop two major effector cell types of the immune system (T cells and NK cells) and suffer from a functional B cell defect. Although drugs such as antibiotics can offer partial protection, the boys normally die in the first year of life in the absence of a curative therapy. For a third of the children, bone marrow transplantation from a fully matched donor is available and can cure the disease without major side effects. Mismatched bone marrow transplantation, however, is complicated by severe and potentially lethal side effects. Over the past decade, scientists worldwide have developed new treatments by introducing a correct copy of the IL2RG-cDNA. Gene therapy was highly effective when applied in young children. However, in a few patients the IL2RG-gene vector has unfortunately caused leukaemia. Activation of cellular proto-oncogenes by accidental integration of the gene vector has been identified as the underlying mechanism. In future clinical trials, improved vector technology in combination with other protocol modifications may reduce the risk of this side effect.
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PMID:[Gene therapy of SCID-X1]. 1804 20

Gene therapy trials have been performed with virus-based vectors that have the ability to integrate permanently into genomic DNA and thus allow prolonged expression of corrective genes after transduction of hematopoietic stem and progenitor cells. Adverse events observed during the X-linked severe combined immunodeficiency gene therapy trial revealed a significant risk of genotoxicity related to retrovirus vector integration and activation of adjacent proto-oncogenes, with several cases of T-cell leukemia linked to vector activation of the LMO2 gene. In patients with chronic granulomatous disease (CGD), rhesus macaques, and mice receiving hematopoietic stem and progenitor cells transduced with retrovirus vectors, a highly non-random pattern of vector integration has been reported. The most striking finding has been overrepresentation of integrations in one specific genomic locus, a complex containing the MDS1 and the EVI1 genes. Most evidence suggests that this overrepresentation is primarily due to a modification of primitive myeloid cell behavior by overexpression of EVI1 or MDS1-EVI1, as opposed to a specific predilection for integration at this site. Three different proteins can be produced from this complex locus: MDS1, MDS1-EVI1, and EVI1. This review will summarize current knowledge regarding this locus and its gene products, with specific focus on issues with relevance to gene therapy, leukemogenesis, and hematopoiesis. Insights into the mechanisms that result in altered hematopoiesis and leukemogenesis when this locus is dysregulated could improve the safety of gene therapy in the future.
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PMID:The MDS1-EVI1 gene complex as a retrovirus integration site: impact on behavior of hematopoietic cells and implications for gene therapy. 1822 42

The recent development of leukemia in gene therapy patients with X-linked severe combined immunodeficiency disease because of retroviral vector insertional mutagenesis has prompted reassessment of the genotoxic potential of integrating vector systems. In this chapter, various strategies are described to reduce the associated risks of retroviral genomic integration. These include deletion of strong transcriptional enhancer-promoter elements in the retroviral long terminal repeats, flanking the retroviral transcriptional unit with enhancer blocking sequences and designing vectors with improved RNA 3' end processing. Protocols are provided to evaluate the relative biosafety of the modified vectors based on their ability to immortalize hematopoietic progenitor cells and propensity to trigger clonal hematopoiesis or leukemogenesis following hematopoietic stem cell transplantation.
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PMID:Reducing the genotoxic potential of retroviral vectors. 1847 Jun 46

Insertional activation of cellular proto-oncogenes by replication-defective retroviral vectors can trigger clonal dominance and leukemogenesis in animal models and clinical trials. Here, we addressed the leukemogenic potential of vectors expressing interleukin-2 receptor common gamma-chain (IL2RG), the coding sequence required for correction of X-linked severe combined immunodeficiency. Similar to conventional gamma-retroviral vectors, self-inactivating (SIN) vectors with strong internal enhancers also triggered profound clonal imbalance, yet with a characteristic insertion preference for a window located downstream of the transcriptional start site. Controls including lentivirally transduced cells revealed that ectopic IL2RG expression was not sufficient to trigger leukemia. After serial bone marrow transplantation involving 106 C57Bl6/J mice monitored for up to 18 months, we observed leukemic progression of six distinct clones harboring gamma-retroviral long terminal repeat (LTR) or SIN vector insertions in Evi1 or Prdm16, two functionally related genes. Three leukemic clones had single vector integrations, and identical clones manifested with a remarkably similar latency and phenotype in independent recipients. We conclude that upregulation of Evi1 or Prdm16 was sufficient to initiate a leukemogenic cascade with consistent intrinsic dynamics. Our study also shows that insertional mutagenesis is required for leukemia induction by IL2RG vectors, a risk to be addressed by improved vector design.
Leukemia 2008 Aug
PMID:Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16. 1849 60

Leukemia caused by retroviral insertional mutagenesis after stem cell gene transfer has been reported in several experimental animals and in patients treated for X-linked severe combined immunodeficiency. Here, we analyzed whether gene transfer into mature T cells bears the same genotoxic risk. To address this issue in an experimental "worst case scenario," we transduced mature T cells and hematopoietic progenitor cells from C57BL/6 (Ly5.1) donor mice with high copy numbers of gamma retroviral vectors encoding the potent T-cell oncogenes LMO2, TCL1, or DeltaTrkA, a constitutively active mutant of TrkA. After transplantation into RAG-1-deficient recipients (Ly5.2), animals that received stem cell transplants developed T-cell lymphoma/leukemia for all investigated oncogenes with a characteristic phenotype and after characteristic latency periods. Ligation-mediated polymerase chain reaction analysis revealed monoclonality or oligoclonality of the malignancies. In striking contrast, none of the mice that received T-cell transplants transduced with the same vectors developed leukemia/lymphoma despite persistence of gene-modified cells. Thus, our data provide direct evidence that mature T cells are less prone to transformation than hematopoietic progenitor cells.
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PMID:Resistance of mature T cells to oncogene transformation. 1877 97


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