Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome
| Autor: | Marco Spinelli, Chiara Brombin, Nufar Marcus, Dario Di Silvestre, Patrizia Della Valle, Lucia Piceni Sereni, Maria Ester Bernardo, Pierluigi Mauri, Francesca Ferrua, Claudio Pignata, Lorella Cattaneo, Alessandro Aiuti, Lucia Dora Notarangelo, Armando D'Angelo, Marita Bosticardo, Stefania Giannelli, Koen van Rossem, Maddalena Migliavacca, Anna Villa, Loris Pozzi, Roula Farah, Maria Carmina Castiello, Maria Pia Cicalese |
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| Přispěvatelé: | Sereni, L., Castiello, M. C., Di Silvestre, D., Della Valle, P., Brombin, C., Ferrua, Paolo, Cicalese, M. P., Pozzi, L., Migliavacca, M., Bernardo, M. E., Pignata, C., Farah, R., Notarangelo, L. D., Marcus, N., Cattaneo, L., Spinelli, M., Giannelli, S., Bosticardo, M., van Rossem, K., D'Angelo, A., Aiuti, A., Mauri, P., Villa, A. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male δ-g Electron-dense granule P-selectin Wiskott–Aldrich syndrome Genetic enhancement sCD40L Soluble CD40 ligand vWF von Willebrand factor HSCT Hematopoietic stem cell transplantation LV Lentivirus 0302 clinical medicine Immunology and Allergy Medicine MFI Mean fluorescence intensity Platelet Child platelet biology Wiskott-Aldrich syndrome Hematopoietic Stem Cell Transplantation X-linked thrombocytopenia Phenotype gene therapy 3. Good health 030220 oncology & carcinogenesis Child Preschool platelets Female PRP Platelet-rich plasma Wiskott-Aldrich Syndrome Protein Adult Blood Platelets BAFF B cell–activating factor Adolescent Immunology Article ADP Adenosine diphosphate 03 medical and health sciences CD62P P-selectin Von Willebrand factor XLT X-linked thrombocytopenia Microscopy Electron Transmission WASp Wiskott-Aldrich syndrome protein HMGB1 High-mobility group box 1 Humans B-cell activating factor GT Gene therapy business.industry TEM Transmission electron microscopy Platelet Count Lentivirus FU Follow-up Infant Genetic Therapy medicine.disease Platelet Activation OCS Open canalicular system STAT3 Signal transducer and activator of transcription 3 030104 developmental biology CT Closure time GPX1 Glutathione peroxidase 1 Platelet-rich plasma sCD62P Soluble P-selectin FERMT3 Fermitin family homolog 3 WAS Wiskott-Aldrich syndrome biology.protein business HD Healthy donor ROS Reactive oxygen species |
| Zdroj: | Journal of allergy and clinical immunology 144 (2019): 825–838. doi:10.1016/j.jaci.2019.03.012 info:cnr-pdr/source/autori:Sereni L1, Castiello MC1, Di Silvestre D2, Della Valle P3, Brombin C4, Ferrua F5, Cicalese MP6, Pozzi L3, Migliavacca M6, Bernardo ME6, Pignata C7, Farah R8, Notarangelo LD9, Marcus N10, Cattaneo L11, Spinelli M12, Giannelli S1, Bosticardo M1, van Rossem K13, D'Angelo A3, Aiuti A5, Mauri P2, Villa A14./titolo:Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome/doi:10.1016%2Fj.jaci.2019.03.012/rivista:Journal of allergy and clinical immunology/anno:2019/pagina_da:825/pagina_a:838/intervallo_pagine:825–838/volume:144 The Journal of Allergy and Clinical Immunology |
| Popis: | 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 defects in terms of phenotype and function in untreated patients with WAS and assessed the effect of GT treatment on platelet dysfunction. METHODS: We analyzed a cohort of 20 patients with WAS/XLT, 15 of them receiving GT. Platelet phenotype and function were analyzed by using electron microscopy, flow cytometry, and an aggregation assay. Platelet protein composition was assessed before and after GT by means of proteomic profile analysis. RESULTS: We show that platelets from untreated patients with WAS have reduced size, abnormal ultrastructure, and a hyperactivated phenotype at steady state, whereas activation and aggregation responses to agonists are decreased. GT restores platelet size and function early after treatment and reduces the hyperactivated phenotype proportionally to WAS protein expression and length of follow-up. CONCLUSIONS: Our study highlights the coexistence of morphologic and multiple functional defects in platelets lacking WAS protein and demonstrates that GT normalizes the platelet proteomic profile with consequent restoration of platelet ultrastructure and phenotype, which might explain the observed reduction of bleeding episodes after GT. These results are instrumental also from the perspective of a future clinical trial in patients with XLT only presenting with microthrombocytopenia. |
| Databáze: | OpenAIRE |
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