Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector

Gaspar, H. Bobby; Parsley, Kathryn L.; Howe, Steven J.; King, Doug; Gilmour, Kimberly C.; Sinclair, Joanna; Brouns, Gaby; Schmidt, Manfred; Kalle, Christof von; Barington, Torben; Jakobsen, Marianne Antonius; Christensen, Hans Ole; Ghonaium, Abdulaziz Al; White, Harry N; Smith, Joan K.; Levinsky, Roland J.; Ali, Robin R.; Kinnon, Christine; Thrasher, Adrian J.

doi:10.1016/s0140-6736(04)17590-9

Cited by 626 publications

(410 citation statements)

References 18 publications

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“…One of the first gene therapy protocols that showed a lasting therapeutic benefit involved the use of a gammaretroviral vector to deliver the common g-chain gene (IL2RG) into the haematopoietic stem cells of children with lethal X-linked severe combined immunodeficiency (X-SCID). 1,2 In the majority of patients a restoration of the immune system was observed, resulting in substantially increased longevity, and most treated patients are still alive today. However, in recent X-SCID gene therapy trials several cases of iatrogenic acute lymphoblastic leukaemia were reported after ex vivo retroviral transduction of the bone marrow cells.…”

Section: Introductionmentioning

confidence: 99%

Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice

Balaggan

Durán²,

Georgiadis³

et al. 2011

Gene Ther

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Insertional mutagenesis following gene therapy with gammaretroviral vectors can cause the development of lymphoproliferation in children with X-linked severe combined immunodeficiency. In experimental studies, recombinant adeno-associated virus (rAAV) vectors have also been reported to increase susceptibility to carcinogenesis. The possibility of vector-induced transformation in quiescent ocular cells is probably significantly lower than in mitotically active cells, but given the increasing number of clinical applications of rAAV and lentiviral vectors for ocular disease, a specific assessment of their oncogenic potential in the eye is important. In this study, we investigated the effect of rAAV2/2 and integrating HIV-1 vectors upon the incidence of ocular neoplasia in p53 tumour-suppressor gene-knockout (p53 À/À ) mice, which are highly susceptible to intraocular malignant transformation. Subretinal injections of high titre rAAV2/2 or integrating HIV-1 vectors induced no tumours in p53 À/À or p53 +/À animals, nor significantly affected their natural longevity. We conclude that any insertional events arising from subretinal delivery of these vectors appear insufficient to cause intraocular malignancy, even in highly susceptible animals. These findings support the continued development of these vectors for ocular applications.

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Section: Introductionmentioning

confidence: 99%

Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice

Balaggan

Durán²,

Georgiadis³

et al. 2011

Gene Ther

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“…7 In addition, retrovirus has been used widely to transduce tumor cells and immune cells for cancer therapy. [8][9][10] Retroviral vectors have also been used successfully in human trials to correct gene deficiencies in diseases including ADA-SCID, [11][12][13][14] X-linked SCID 15,16 and chronic granulomatous disease. 17 Retroviruses insert their genes in a semirandom manner into host chromosomes, 18 and it is thought that retroviruses may integrate preferentially into transcriptionally active sites.…”

Section: Introductionmentioning

confidence: 99%

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

Westwood

Murray²,

Trivett³

et al. 2008

Gene Ther

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There is considerable concern regarding the transforming potential of retroviral vectors currently used for gene therapy, with evidence that retroviral integration can lead to leukemia in recipients of gene-modified stem cells. However, it is not clear whether retroviral-mediated transduction of T cells can lead to malignancy. We transduced mouse T cells with a Moloney murine retroviral gene construct and transferred them into congenic mice, which were preconditioned to enhance the engraftment of transferred T cells. Recipients were then observed long-term for evidence of cancer. Transferred T cells persisted in mice throughout life at levels up to 17% with gene copy numbers up to 5.89 Â 10 5 per million splenocytes. Mice receiving gene-modified T cells developed tumors at a similar rate as control mice that did not receive T cells, and tumors in both groups of mice were of a similar range of histologies. Hematological malignancies comprised approximately 60% of cancers, and the remaining cancers consisted largely of carcinomas. Importantly, the incidence of lymphomas was similar in both groups of mice, and no lymphomas were found to be of donor T-cell origin. This study indicates that the use of retroviral vectors to transduce T cells does not lead to malignant transformation.

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“…[58][59][60] These hematological disorders were attributed to the so-called insertional mutagenesis which means that the promoter driving the transgenes influences the expression of genes in the host genome in the vicinity of the integrated provirus. Although intense analyses revealed that additional genomic instabilities were involved in the progression of these leukemic clones, 61,62 further vector improvement is urgently needed.…”

Section: Discussionmentioning

confidence: 99%

F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells

et al. 2012

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Chemoprotection of haematopoietic stem cells (HSCs) by gene therapeutic transfer of drug-resistance genes represents the encouraging approach to prevent myelosuppression, which is one of the most severe side effects in tumor therapy. Thus, we cloned and evaluated six different bicistronic lentiviral SIN vectors encoding two transgenes, MGMT P140K (an O 6 -benzylguanineresistant mutant of methylguanine-DNA methyltransferase) and MDR1 (multidrug resistance 1), using various linker sequences (IRESEMCV, IRESFMDV and 2A-element of FMDV (F2A)). Expression of both transgenes in HL-60 and in K562 cells was assayed by quantitative real-time PCR. Combination therapy with ACNU plus paclitaxel in HL-60 cells and with carmustin (BCNU) plus doxorubicin in K562 cells resulted in the most significant survival advantage of cells transduced with the lentiviral vector HR'SIN-MGMT P140K -F2A-MDR1 compared with untransduced cells. In human HSCs, overexpression of both transgenes by this vector also caused significantly increased survival and enrichment of transduced cells after treatment with BCNU plus doxorubicin or temozolomide plus paclitaxel. In summary, we could show significant chemoprotection by overexpression of MDR1 and MGMT P140K with a lentiviral vector using the F2A linker element in two different haematopoietic cell lines and in human primary HSCs with various combination regimens. Consequently, we are convinced that these in vitro investigations will help to improve combination chemotherapy regimens by reducing myelotoxic side effects and increasing the therapeutic efficiency.

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Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector

Cited by 626 publications

References 18 publications

Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice

Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells

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