Publication Date:
2013-07-13
Description:
Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375961/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375961/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aiuti, Alessandro -- Biasco, Luca -- Scaramuzza, Samantha -- Ferrua, Francesca -- Cicalese, Maria Pia -- Baricordi, Cristina -- Dionisio, Francesca -- Calabria, Andrea -- Giannelli, Stefania -- Castiello, Maria Carmina -- Bosticardo, Marita -- Evangelio, Costanza -- Assanelli, Andrea -- Casiraghi, Miriam -- Di Nunzio, Sara -- Callegaro, Luciano -- Benati, Claudia -- Rizzardi, Paolo -- Pellin, Danilo -- Di Serio, Clelia -- Schmidt, Manfred -- Von Kalle, Christof -- Gardner, Jason -- Mehta, Nalini -- Neduva, Victor -- Dow, David J -- Galy, Anne -- Miniero, Roberto -- Finocchi, Andrea -- Metin, Ayse -- Banerjee, Pinaki P -- Orange, Jordan S -- Galimberti, Stefania -- Valsecchi, Maria Grazia -- Biffi, Alessandra -- Montini, Eugenio -- Villa, Anna -- Ciceri, Fabio -- Roncarolo, Maria Grazia -- Naldini, Luigi -- R01 AI067946/AI/NIAID NIH HHS/ -- TGT11D01/Telethon/Italy -- TGT11D02/Telethon/Italy -- New York, N.Y. -- Science. 2013 Aug 23;341(6148):1233151. doi: 10.1126/science.1233151. Epub 2013 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells, and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. aiuti.alessandro@hsr.it〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23845947" target="_blank"〉PubMed〈/a〉
Keywords:
Child
;
Genetic Therapy/*methods
;
Genetic Vectors
;
*Hematopoietic Stem Cell Transplantation
;
Hematopoietic Stem Cells/*metabolism
;
Humans
;
Lentivirus
;
Male
;
Transduction, Genetic
;
Virus Integration
;
Wiskott-Aldrich Syndrome/*therapy
;
Wiskott-Aldrich Syndrome Protein/*genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
