{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T09:02:55Z","timestamp":1792918975001,"version":"4.5.0"},"reference-count":41,"publisher":"Georg Thieme Verlag KG","issue":"11","license":[{"start":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T00:00:00Z","timestamp":1734998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:p>Wiskott\u2013Aldrich syndrome (WAS) is a severe X-linked disorder caused by loss-of-function mutations in the WAS gene, responsible for encoding WAS protein (WASP), a key regulator of the actin cytoskeleton in all hematopoietic cells, except red blood cells. The mechanism underlying microthrombocytopenia, a distinctive feature of WAS and a major contributor to mortality, remains not fully elucidated. In this study, using different gene-editing strategies, we corrected mutations in patient-derived WAS-induced pluripotent stem cell (iPSC) lines, generating isogeneic WAS-iPSC lines. These included lines with direct mutation-specific correction and lines incorporating a WASP transgene cassette regulated by the MND or WAS1.6\u2009kb promoter integrated at the safe harbor AAV1 site. Our results demonstrated that direct mutation correction successfully restored WASP levels to the equivalent of the wild-type in iPSC-derived megakaryocytes (MKs). In contrast, the AAV1-targeted strategy using the MND and WAS1.6 promoters yielded a lower level of WASP. Notably, only the mutation-specific correction lines exhibited improvements in proplatelet structures and generated larger-sized platelets. Our findings underscore the crucial roles of WASP during human thrombopoiesis and suggest that therapeutic approaches, such as direct gene correction, which can achieve physiologic levels of WASP in MKs, hold promise for ameliorating platelet defects in individuals with WAS.<\/jats:p>","DOI":"10.1055\/a-2508-0983","type":"journal-article","created":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T19:00:21Z","timestamp":1735066821000},"page":"1115-1126","source":"Crossref","is-referenced-by-count":2,"title":["Gene Correction of Wiskott\u2013Aldrich syndrome iPS Cells Rescues Proplatelet Defects and Improves Platelet Size"],"prefix":"10.1055","volume":"125","author":[{"given":"Praewphan","family":"Ingrungruanglert","sequence":"additional","affiliation":[{"name":"Center of Excellence for Stem Cell and Cell Therapy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"},{"name":"Excellence Center for Stem Cell and Cell Therapy, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarinya","family":"Phodang","sequence":"additional","affiliation":[{"name":"Center of Excellence for Stem Cell and Cell Therapy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"},{"name":"Excellence Center for Stem Cell and Cell Therapy, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pramuk","family":"Amarinthnukrowh","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Center of Excellence for Medical Genomics, Medical Genomics Cluster, Chulalongkorn University, Bangkok, Thailand"},{"name":"Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phattarawan","family":"Meehart","sequence":"additional","affiliation":[{"name":"Center of Excellence for Stem Cell and Cell Therapy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"},{"name":"Excellence Center for Stem Cell and Cell Therapy, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pornpitra","family":"Pratedrat","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Science, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narissara","family":"Suratannon","sequence":"additional","affiliation":[{"name":"Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Faculty of Medicine, Center of Excellence for Allergy and Clinical Immunology, Chulalongkorn University, Bangkok, Thailand"},{"name":"King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vorasuk","family":"Shotelersuk","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Center of Excellence for Medical Genomics, Medical Genomics Cluster, Chulalongkorn University, Bangkok, Thailand"},{"name":"Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanya","family":"Suphapeetiporn","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Center of Excellence for Medical Genomics, Medical Genomics Cluster, Chulalongkorn University, Bangkok, Thailand"},{"name":"Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1954-6567","authenticated-orcid":false,"given":"Nipan","family":"Israsena","sequence":"additional","affiliation":[{"name":"Center of Excellence for Stem Cell and Cell Therapy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"},{"name":"Excellence Center for Stem Cell and Cell Therapy, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"},{"name":"Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2025,2,25]]},"reference":[{"issue":"01","key":"ref1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s10875-017-0453-z","article-title":"Clinical manifestations and pathophysiological mechanisms of the Wiskott-Aldrich syndrome","volume":"38","author":"F Candotti","year":"2018","journal-title":"J Clin Immunol"},{"issue":"03","key":"ref2","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nri2724","article-title":"WASP: a key immunological multitasker","volume":"10","author":"A J Thrasher","year":"2010","journal-title":"Nat Rev Immunol"},{"issue":"04","key":"ref3","doi-asserted-by":"crossref","first-page":"e13951","DOI":"10.1111\/pai.13951","article-title":"Understanding immunoactinopathies: a decade of research on WAS gene defects","volume":"34","author":"R C Vieira","year":"2023","journal-title":"Pediatr Allergy Immunol"},{"issue":"13","key":"ref4","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1182\/blood.2021014687","article-title":"Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome: an EBMT Inborn Errors Working Party analysis","volume":"139","author":"M H 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