Functional correction of T cells derived from patients with the Wiskott–Aldrich syndrome (WAS) by transduction with an oncoretroviral vector encoding the WAS protein

Strom, Ted S.; Gabbard, Wesley; Kelly, Patrick; Cunningham, John M.; Nienhuis, Arthur W.

doi:10.1038/sj.gt.3301950

Cited by 53 publications

(34 citation statements)

References 29 publications

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“…Expression of the WASP transgene confers a selective growth advantage to transduced T cells as described in spontaneous reversions of WAS patients [29][30][31] as well as in other models of CD3-activated WASp + cells. 32,33 This observation indicates that the protein expressed in WW-transduced cells is functional. Furthermore, we have found that transduction of WAS-deficient T cells with the WW vector results in full reconstitution of cellular defects, including restoration of morphology and CD3-mediated responses (our unpublished data).…”

Section: Lentiviral Vectors Transcriptionally Targeted To Hematopoietmentioning

confidence: 87%

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Lentiviral vectors transcriptionally targeted to hematopoietic cells by WASP gene proximal promoter sequences

et al. 2005

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Section: Lentiviral Vectors Transcriptionally Targeted To Hematopoietmentioning

confidence: 87%

“…[29][30][31][32][33] Therefore, HVS-WAS/1 cells were transduced with the WW lentiviral vector at MOIs of 0.01, 0.1 and 1 and kept in culture for 39 days. The percentage of WASpexpressing cells was analyzed by flow cytometry at days 7, 27 and 39 after transduction.…”

Section: Wasp Expression Confers a Selective Growth Advantage To Ww-tmentioning

confidence: 99%

Lentiviral vectors transcriptionally targeted to hematopoietic cells by WASP gene proximal promoter sequences

et al. 2005

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“…Primary T cells from patients with WAS have impaired IL-2 gene expression after stimulation by immobilized anti-CD3 mAb (26), and herpes virus saimiri-transformed T cell lines from these patients have a defect in polymerizing actin after TCR ligation (6). Because the proteasome inhibitor bortezomib was not toxic to murine T cells in the first 6 h, we examined its ability to correct the functional defect in primary T cells from the patient with the R86H mutation in WASP.…”

Section: Il-2 Expression By T Cells With R86h Mutation In Waspmentioning

confidence: 99%

WIP is a chaperone for Wiskott–Aldrich syndrome protein (WASP)

Fuente

Sasahara

Calamito

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

148

172

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Wiskott–Aldrich syndrome protein (WASP) is in a complex with WASP-interacting protein (WIP). WASP levels, but not mRNA levels, were severely diminished in T cells from WIP −/− mice and were increased by introduction of WIP in these cells. The WASP binding domain of WIP was shown to protect WASP from degradation by calpain in vitro . Treatment with the proteasome inhibitors MG132 and bortezomib increased WASP levels in T cells from WIP −/− mice and in T and B lymphocytes from two WAS patients with missense mutations (R86H and T45M) that disrupt WIP binding. The calpain inhibitor calpeptin increased WASP levels in activated T and B cells from the WASP patients, but not in primary T cells from the patients or from WIP −/− mice. Despite its ability to increase WASP levels proteasome inhibition did not correct the impaired IL-2 gene expression and low F-actin content in T cells from the R86H WAS patient. These results demonstrate that WIP stabilizes WASP and suggest that it may also be important for its function.

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“…Preclinical studies have shown that retroviral transduction corrects the immunologic defect in WASP knockout mice and in human cell lines, with increased actin polymerization and functional correction of T cells after transduction. [65][66][67][68] Gene therapy clinical trials have not been performed yet.…”

Section: Wasmentioning

confidence: 99%