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Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome
- Source :
- 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
- Publication Year :
- 2019
- Publisher :
- Mosby, St. Louis, Mo. , Stati Uniti d'America, 2019.
-
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 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- 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
- Accession number :
- edsair.doi.dedup.....8fbef2a3b9359481a3aee0ecf5da45bb