Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial

Muul, Linda; Tuschong, Laura M.; Soenen, Sherry L.; Jagadeesh, G. Jayashree; Ramsey, W. Jay; Zhang, Long; Carter, Charles S.; Garabedian, Elizabeth; Alleyne, Melinna; Brown, Margaret R.; Bernstein, Wendy B.; Schurman, Shepherd H.; Fleisher, Thomas A.; Leitman, Susan F.; Dunbar, Cynthia E.; Blaese, R. Michael; Candotti, Fabio

doi:10.1182/blood-2002-09-2800

Cited by 193 publications

(122 citation statements)

References 29 publications

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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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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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“…Transduced cells were reinfused into the subjects, in whom new ADA expression could subsequently be detected for up to 12 years. 29,30 The patients experienced no ill effects and have remained in stable condition. However, the gene transfer was not efficient enough to produce clinical benefit.…”

Section: Progress Of Gene Therapy For Primary Immunodeficiencies Adenmentioning

confidence: 99%

“…PEG-ADA therapy significantly increases the numbers of T and B cells of most patients with ADA deficiency and therefore removes the selective advantage that the gene-corrected cells might have. Among the important observations arising from this trial were the documentation of the longevity of correction in transduced and differentiated T cells (one patient still carries the transduced gene in approximately 20% of her peripheral blood lymphocytes), 30 as well as the development of antibodies to FCS that were used during the ex vivo culture. 32 FCS has been omitted from subsequent trials.…”

Section: Progress Of Gene Therapy For Primary Immunodeficiencies Adenmentioning

confidence: 99%

Successes and risks of gene therapy in primary immunodeficiencies

Chinen

Puck

2004

Journal of Allergy and Clinical Immunology

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“…From a strictly virological perspective, viral tropism refers to all cell types in which virus entry leads to the production of viral progeny, or cell types that maintain this production potential with 'dormant' viruses. As for all retroviruses, this is of particular importance in the context of HTLV, due to the stable integration of the viral genome in infected cells including T lymphocytes, whose in vivo lifespan may exceed a decade (Muul et al, 2003). Pathogenic effects are thus additional properties, that obviously depend directly on cell tropism but that, strictly speaking, do not participate in its definition.…”

Section: Cell Type-specific Pathogenesis Versus Tropismmentioning

confidence: 99%

HTLV-1 tropism and envelope receptor

et al. 2005

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The identification of CD4 as the primary receptor for HIV followed shortly after the discovery of the virus, but the HTLV receptor remained long elusive, until its recent identification as the GLUT1 glucose transporter. In the present review, we describe the status of the literature that surrounded this discovery as well as the in vitro and in vivo observations that led to the identification of GLUT1. Also, we will explore a few tracks to conciliate the in vitro and in vivo data on HTLV-1 tropism within the context of the HTLV literature that has accumulated over the past 25 years. A close examination of these data leads us to conclude that the preferential detection of HTLV-1 in CD4 þ T lymphocyte subsets in vivo, even in the absence of leukemia, is not likely to be directly related to envelope receptor interactions, but rather to an array of postentry selection bottlenecks in vivo. Furthermore, we propose that infection of other hematopoietic and nonhematopoietic cells is likely to take place during the lifetime of an individual, with a burst early during the infection. Oncogene (2005) 24, 6016-6025.

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Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial

Cited by 193 publications

References 29 publications

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

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

Successes and risks of gene therapy in primary immunodeficiencies

HTLV-1 tropism and envelope receptor

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