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Query: UMLS:C0085110 (SCID)
 11,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.
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PMID:LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. 1456 94

The LMO2 gene encodes a LIM-only protein and is a target of chromosomal translocations in human T-cell leukemia. Recently, two X-SCID patients treated by gene therapy to rescue T-cell lymphopoiesis developed T-cell leukemias with retroviral insertion into the LMO2 gene causing clonal T-cell proliferation. In view of the specificity of LMO2 in T-cell tumorigenesis, we investigated a possible role for Lmo2 in T-lymphopoiesis, using conditional knockout of mouse Lmo2 with loxP-flanked Lmo2 and Cre recombinase alleles driven by the promoters of the lymphoid-specific genes Rag1, CD19, and Lck. While efficient deletion of Lmo2 was observed, even in the earliest detectable lymphoid cell progenitors of the bone marrow, there was no disturbance of lymphopoiesis in either T- or B-cell lineages, and in contrast to Lmo2 transgenic mice, there were normal distributions of CD4- CD- thymocytes. We conclude that there is no mandatory role for LMO2 in lymphoid development, implying that its specific role in T-cell tumorigenesis results from a reprogramming of gene expression after enforced expression in T-cell precursors.
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PMID:The LMO2 T-cell oncogene is activated via chromosomal translocations or retroviral insertion during gene therapy but has no mandatory role in normal T-cell development. 1464 13

Several primary immunodeficiencies are under consideration for gene therapy approaches because of limitations of current standard treatment. Many primary immunodeficiencies are caused by defects in single genes expressed in blood cells; thus addition of a correct copy of the gene to hematopoietic stem cells (HSCs) can generate immune cells with restored function. HSCs can be removed from a patient, treated outside the body, and reinfused. In the last decade, significant improvements have been made in transferring genes by means of retroviruses to HSCs in vitro, and gene therapy trials for patients with X-linked severe combined immunodeficiency (XSCID) and adenosine deaminase-deficient severe combined immunodeficiency have restored immune competence. Gene therapy is actively being pursued in other immunodeficiency disorders, including chronic granulomatous disease and Wiskott-Aldrich syndrome. However, enthusiasm for the correction of XSCID by means of gene therapy has been tempered by the occurrence of 2 cases of leukemia in gene therapy recipients caused by insertion of the retroviral vector in or near the oncogene LMO2. The likelihood of retroviral insertional mutagenesis was estimated to be very low in the past on the basis of theoretic calculations and the absence of observed malignancies in animal studies and early clinical trials. Emerging new findings on retroviral integration both in the patients with XSCID and experimental animals now indicate that the insertion of retroviral sequences into the genome carries significant risk. Understanding the magnitude of risk is now a priority so that safety can be improved for future gene therapy clinical trials.
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PMID:Successes and risks of gene therapy in primary immunodeficiencies. 1510 Jun 60

Two serious adverse events involving activation of the LMO2 oncogene through retrovirus vector insertion in the otherwise extremely successful first gene therapy trial for X-linked severe combined immunodeficieny type 1 (SCID-X1) had initially caused widespread concern in the patient and research communities. Careful consideration 1 year after diagnosis of the second case still finds 12 of the treated patients clearly benefiting from gene therapy (freedom from treatment failure, 80%; survival 100%), a situation that should not portend the end of gene therapy for this disease, and is, in fact encouraging. While current approaches are justified to treat patients with otherwise life-threatening disorders, a broad consensus has developed that systematic basic research is required to further understand the pathophysiology of these serious adverse events and to provide new insights, enabling safer and more effective gene therapy strategies. With the continued success of SCID-X1 gene therapy in the majority of patients treated, it is of even greater importance to understand exactly which vector element or combination of elements predispose to toxicity. An in-depth study of the mechanisms behind the activation of the LMO2 and gammac genes will be highly instructive for the development of safer procedures and vectors. We summarize the central observations, ongoing experimental approaches, new concepts, and developments relevant to understanding, interpreting, and eventually overcoming the real and perceived obstacles posed by insertional mutagenesis due to gene transfer vectors.
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PMID:Stem cell clonality and genotoxicity in hematopoietic cells: gene activation side effects should be avoidable. 1550 16

When a retrovirus infects a cell, its RNA genome is reverse transcribed into a double-stranded DNA, which is then permanently integrated into the host chromosome. Integration is one of the essential steps in the retroviral life cycle. Many transposable elements also move around and integrate into the host genome as part of their life cycle, some through RNA intermediates and some through 'cut and paste' mechanisms. Integration of retroviruses and transposable elements into 'sensitive areas' of the genome can cause irreparable damage. On the other hand, because of their ability to integrate permanently, and the relatively efficient rates of transgenesis, retroviruses and transposable elements are widely used as gene delivery tools in basic research and gene therapy trials. Recent events in gene therapy treatments for X-linked severe combined immunity deficiencies (X-SCID) have highlighted both the promise and some of the risks involved with utilizing retroviruses. Nine of 11 children were successfully treated for X-SCID using a retrovirus carrying the gene mutated in this disease. However, later two of these children developed leukemias because of retroviral integrations in the putative oncogene LMO2 [1]. A third child has also been demonstrated to have an integration in LMO2, but is as of yet nonsymptomatic [2]. It is a bit difficult to explain the high frequency of integrations into the same gene using a random model of retroviral integration, and there has been evidence for decades that retroviral integrations may not be random. But the data were somewhat limited in their power to determine the precise nature of the integration biases. The completion of the human genome sequence coupled with sensitive polymerase chain reaction techniques and an ever-decreasing cost of sequencing has given a powerful new tool to the study of integration site selection. In this review, we describe the findings from several recent global surveys of target site selection by retroviruses and transposable elements, and discuss the possible ramifications of these findings to both mechanisms of action and to the use of these elements as gene therapy vectors.
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PMID:Integration target site selection for retroviruses and transposable elements. 1552 64

Chromosomal translocations are primary events in the development of leukemias, representing at least one genetic feature of the putative cancer stem cell. Studies of genes influenced by chromosomal translocations have yielded a vast amount of information about how cancer is initiated and maintained. In particular, acute leukemias have demonstrated that chromosomal translocations often involve transcription regulators that function by interacting with proteins and by controlling cell fate in the aberrant setting of the developing cancer cell. As a quintessential chromosomal translocation gene product, LMO2 has many properties that typify this class of molecule. In addition to its involvement in chromosomal translocations, the LMO2 gene was inadvertently activated in an X-SCID gene therapy trial by retroviral insertion. New molecular therapies targeted directly at the LMO2 protein could have major impact as adjuncts to existing therapies or as therapeutics in their own right. In this review, we outline the current knowledge about LMO2 and some possible routes to develop reagents that might be possible macromolecular drugs in the future.
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PMID:The role of LMO2 in development and in T cell leukemia after chromosomal translocation or retroviral insertion. 1626 Jan 84

Following gene therapy of SCID-X1 using murine leukemia virus (MLV) derived vector, two patients developed leukemia owing to an activating vector integration near the LMO2 gene. We found that these integrations reside within FRA11E, a common fragile site known to correlate with chromosomal breakpoints in tumors. Further analysis showed that fragile sites attract a nonrandom number of MLV integrations, shedding light on its integration mechanism and risk-to-benefit ratio in gene therapy.
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PMID:Fragile sites are preferential targets for integrations of MLV vectors in gene therapy. 1651 18

Although gene therapy can cure patients with severe combined immunodeficiency (SCID) syndromes, the clinical occurrence of T cell malignancies due to insertional mutagenesis has raised concerns about the safety of gene therapy. Several key questions have remained unanswered: (i) are there unique risk factors for X-linked SCID (XSCID) gene therapy that increase the risk of insertional mutagenesis; (ii) what other genetic lesions may contribute to transformation; and (iii) what systems can be used to test different vectors for their relative safety? To address these questions, we have developed an XSCID mouse model in which both the Arf tumor-suppressor gene and the gammac gene were ablated. Gene therapy in this animal model recapitulates the high incidence of integration-dependent, T cell tumors that was seen in the clinical trial. Ligation-mediated PCR analysis showed integration sites near or within established protooncogenes (Chd9, Slamf6, Tde1, Camk2b, and Ly6e), demonstrating that T cell transformation was associated with targeting of oncogene loci; however, no integrations within the Lmo2 locus were identified. The X-SCID background in transplanted cells was required for high rate transformation and was associated with expansion of primitive hematopoietic cells that may serve tumor precursors. This model should be useful for testing safety-modified vectors and for further exploring the risk factors leading to insertional mutagenesis in gene therapy trials.
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PMID:Unique risk factors for insertional mutagenesis in a mouse model of XSCID gene therapy. 1686 81

The gene IL2RG encodes the gamma-chain of the interleukin-2 receptor and is mutated in patients with X-linked severe combined immune deficiency (X-SCID). Woods et al. report the development of thymus tumours in a mouse model of X-SCID after correction by lentiviral overexpression of IL2RG and claim that these were caused by IL2RG itself. Here we find that retroviral overexpression of IL2RG in human CD34+ cells has no effect on T-cell development, whereas overexpression of the T-cell acute lymphoblastic leukaemia (T-ALL) oncogene LMO2 leads to severe abnormalities. Retroviral expression of IL2RG may therefore not be directly oncogenic--rather, the restoration of normal signalling by the interleukin-7 receptor to X-SCID precursor cells allows progression of T-cell development to stages that are permissive for the pro-leukaemic effects of ectopic LMO2.
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PMID:Gene therapy: is IL2RG oncogenic in T-cell development? 1664 81

Gene transfer into HSCs is an effective treatment for SCID, although potentially limited by the risk of insertional mutagenesis. We performed a genome-wide analysis of retroviral vector integrations in genetically corrected HSCs and their multilineage progeny before and up to 47 months after transplantation into 5 patients with adenosine deaminase-deficient SCID. Gene-dense regions, promoters, and transcriptionally active genes were preferred retroviral integrations sites (RISs) both in preinfusion transduced CD34(+) cells and in vivo after gene therapy. The occurrence of insertion sites proximal to protooncogenes or genes controlling cell growth and self renewal, including LMO2, was not associated with clonal selection or expansion in vivo. Clonal analysis of long-term repopulating cell progeny in vivo revealed highly polyclonal T cell populations and shared RISs among multiple lineages, demonstrating the engraftment of multipotent HSCs. These data have important implications for the biology of retroviral vectors, the dynamics of genetically modified HSCs, and the safety of gene therapy.
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PMID:Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. 1767 45


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