2019
DOI: 10.1016/j.jaci.2019.03.012
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Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome

Abstract: Background Thrombocytopenia is a serious issue for all patients with classical Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) because it causes severe and life-threatening bleeding. Lentiviral gene therapy (GT) for WAS has shown promising results in terms of immune reconstitution. However, despite the reduced severity and frequency of bleeding events, platelet counts remain low in GT-treated patients. Objective We carefully investigated platelet defe… Show more

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Cited by 50 publications
(52 citation statements)
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“…The fundamental pathogenesis of platelet defects in WAS is still largely elusive, but both ineffective platelet production and their accelerated elimination in periphery have been implicated [26][27][28] . The former hypothesis has been confirmed by recent studies highlighting the presence of platelet-intrinsic defects that may accelerate their clearance 29,30 , such as a reduced size and granularity, dysregulated activation at steady state (high CD62P expression) and increased phosphatidylserine exposure which in turn may lead to increased platelet phagocytosis. To determine the ability of our gene editing strategy to correct the abnormalities observed in this cell lineage, modified WAS HSPCs were also differentiated into platelets and functional correction was tested at this stage.…”
Section: Crispr/cas9-mediated Editing Of the Was Locus In Hspcsmentioning
confidence: 72%
See 1 more Smart Citation
“…The fundamental pathogenesis of platelet defects in WAS is still largely elusive, but both ineffective platelet production and their accelerated elimination in periphery have been implicated [26][27][28] . The former hypothesis has been confirmed by recent studies highlighting the presence of platelet-intrinsic defects that may accelerate their clearance 29,30 , such as a reduced size and granularity, dysregulated activation at steady state (high CD62P expression) and increased phosphatidylserine exposure which in turn may lead to increased platelet phagocytosis. To determine the ability of our gene editing strategy to correct the abnormalities observed in this cell lineage, modified WAS HSPCs were also differentiated into platelets and functional correction was tested at this stage.…”
Section: Crispr/cas9-mediated Editing Of the Was Locus In Hspcsmentioning
confidence: 72%
“…P-values were calculated using oneway ANOVA with Bonferroni's comparison test (a, c, f-j myeloid cells has been linked to persistence of inflammatory complications and autoimmunity 12,13,43 , reliable and robust WASp restoration through a gene editing platform could potentially reduce such risks. Full reconstitution of WASp expression could also contribute to more reliable correction of thrombocytopenia, and therefore to application of this approach to patients with attenuated WAS who predominantly manifest thrombocytopenia and bleeding risk 12,13,29 . Although limited to an in vitro platelet differentiation system, our data suggest that targeted integration of the W-pA cassette can restore normal levels of WASp in megakaryocyte progenitors and mature platelets, correcting the platelet-intrinsic defects observed in WAS patients.…”
Section: Discussionmentioning
confidence: 99%
“…This may also be a result of improved platelet function and phenotype after treatment. 9 Autoimmunity improved after GT, 5,8 tolerance. However, in contrast to the results of other centers, 2 subjects treated in Boston with preexisting autoimmunity had no resolution after GT, in association with poor recovery of lymphocytes, including regulatory T cells.…”
Section: Clinical Gtmentioning
confidence: 96%
“…This was enough to prevent severe bleeding but not to stop bleeding events completely. These results indicate that even after the transduction of multipotent HSCs and their differentiation into hematopoietic lineages (Scala et al, 2018), platelet production does not fully compensate for the destruction of WASp-deficient platelets (Sereni et al, 2019). It may well be that thrombocytopoiesis requires more progenitor cells than lymphopoiesis because of the high platelet turnover.…”
Section: Extension Of Indicationsmentioning
confidence: 99%