T Lymphocyte-Directed Gene Therapy for ADA
            <sup>−</sup>
            SCID: Initial Trial Results After 4 Years

Blaese, R. Michael; Culver, Kenneth W.; Miller, A. Dusty; Carter, Charles S.; Fleisher, Thomas A.; Clerici, Mario; Shearer, Gene M.; Chang, Lauren; Chiang, Yawen; Tolstoshev, Paul; Greenblatt, Jay J.; Rosenberg, Steven A.; Klein, Harvey G.; Berger, Melvin; Mullen, Craig A.; Ramsey, W. Jay; Muul, Linda; Morgan, Richard A.; Anderson, W. French

doi:10.1126/science.270.5235.475

Cited by 1,362 publications

(661 citation statements)

References 61 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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show abstract

“…[1][2][3][4] Moreover, transfer of wild-type genes into T cells with defects in enzymatic genes such as adenosine deaminase may allow the correction of these types of disorders. [5][6][7] At this time, the most widely used method for gene transfer into human T cells has involved Moloney murine leukemia virus (MuLV)-based vectors. MuLVbased vectors allow stable gene transfer as the genetic material contained within the vector is integrated into target cell genomes.…”

Section: Introductionmentioning

confidence: 99%

Lentivirus-mediated gene transfer in primary T cells is enhanced by a central DNA flap

et al. 2001

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Retroviral vectors have become the primary tool for gene delivery into hematopoietic cells, including T lymphocytes. Lentiviral vectors offer an advantage over Moloney murine leukemia virus (MuLV) vectors because of their ability to translocate across an intact nuclear membrane and integrate into the genome of nonproliferating cells. We have recently demonstrated that a central strand displacement event, controlled by the central polypurine tract (cPPT) and the central termination sequence (CTS), results in the formation of a central DNA flap which acts as a cis-determinant of HIV-1 genome nuclear import. Here, we show that insertion of this DNA determinant in a classical lentiviral vector resulted in a significantly higher level of transduction in acti-

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“…9,10 As of now, more than 400 gene therapy clinical trials have been performed worldwide. More than half of these clinical trials were performed for investigating cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Tumor-targeted gene therapy using Adv-AFP-HRPC/IAA prodrug system suppresses growth of hepatoma xenografted in mice

et al. 2011

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Clinical efficacy of current therapies for hepatocellular carcinoma (HCC) treatment is limited. Indole-3-acetic acid (IAA) is non-toxic for mammalian cells. Oxidative decarboxylation of IAA by horseradish peroxidase (HRP) leads to toxic effects of IAA. The purpose of this study was to investigate the effects of a novel gene-targeted enzyme prodrug therapy with IAA on hepatoma growth in vitro and in vivo mouse hepatoma models. We generated a plasmid using adenovirus to express HRP isoenzyme C (HRPC) with the HCC marker, alpha-fetoprotein (AFP), as the promoter (pAdv-AFP-HRPC). Hepatocellular cells were infected with pAdv-AFP-HRPC and treated with IAA. Cell death was detected using MTT assay. Hepatoma xenografts were developed in mice by injection of mouse hepatoma cells. The size and weight of tumors and organs were evaluated. Cell death in tumors was assessed using hematoxylin and eosin-stained tissue sections. HRPC expression in tissues was detected using Reverse Transcriptase-Polymerase Chain Reaction. IAA stimulated death of hepatocellular cells infected with pAdv-AFP-HRPC, in a dose-and time-dependent manner, but not in control cells. Growth of hepatoma xenografts, including the size and weight, was inhibited in mice treated with pAdv-AFP-HRPC and IAA, compared with that in control group. pAdv-AFP-HRPC/IAA treatment induced cell death in hepatoma xenografts in mice. HRPC gene expressed only in hepatoma, but not in other normal organs of mice. pAdv-AFP-HRPC/IAA treatment did not cause any side effects on normal organs. These findings suggest that pAdv-AFP-HRPC/IAA enzyme/prodrug system may serve as a strategy for HCC therapy.

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T Lymphocyte-Directed Gene Therapy for ADA ⁻ SCID: Initial Trial Results After 4 Years

Cited by 1,362 publications

References 61 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

Lentivirus-mediated gene transfer in primary T cells is enhanced by a central DNA flap

Tumor-targeted gene therapy using Adv-AFP-HRPC/IAA prodrug system suppresses growth of hepatoma xenografted in mice

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T Lymphocyte-Directed Gene Therapy for ADA − SCID: Initial Trial Results After 4 Years

Cited by 1,362 publications

References 61 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

Lentivirus-mediated gene transfer in primary T cells is enhanced by a central DNA flap

Tumor-targeted gene therapy using Adv-AFP-HRPC/IAA prodrug system suppresses growth of hepatoma xenografted in mice

Contact Info

Product

Resources

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T Lymphocyte-Directed Gene Therapy for ADA ⁻ SCID: Initial Trial Results After 4 Years