Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome

被引：864

作者：

Aiuti, Alessandro ^{[1
,2
,3
,4
,5
]}

Biasco, Luca ^{[1
]}

Scaramuzza, Samantha ^{[1
]}

Ferrua, Francesca ^{[2
,3
,6
]}

Cicalese, Maria Pia ^{[2
,3
]}

Baricordi, Cristina ^{[1
]}

Dionisio, Francesca ^{[1
]}

Calabria, Andrea ^{[1
]}

Giannelli, Stefania ^{[1
]}

Castiello, Maria Carmina ^{[1
,6
]}

Bosticardo, Marita ^{[1
]}

Evangelio, Costanza ^{[2
,3
]}

Assanelli, Andrea ^{[3
,7
]}

Casiraghi, Miriam ^{[2
]}

Di Nunzio, Sara ^{[2
]}

Callegaro, Luciano ^{[2
]}

Benati, Claudia ^{[8
]}

Rizzardi, Paolo ^{[8
]}

Pellin, Danilo ^{[9
]}

Di Serio, Clelia ^{[9
]}

Schmidt, Manfred ^{[10
]}

Von Kalle, Christof

Gardner, Jason ^{[11
]}

Mehta, Nalini ^{[12
]}

Neduva, Victor ^{[12
]}

Dow, David J. ^{[12
]}

Galy, Anne ^{[13
]}

Miniero, Roberto ^{[14
]}

Finocchi, Andrea ^{[5
]}

Metin, Ayse ^{[15
]}

Banerjee, Pinaki P.

Orange, Jordan S. ^{[16
]}

Galimberti, Stefania ^{[17
]}

Valsecchi, Maria Grazia ^{[3
,17
]}

Biffi, Alessandra ^{[1
,2
,3
]}

Montini, Eugenio ^{[1
]}

Villa, Anna ^{[1
,18
]}

Ciceri, Fabio

Roncarolo, Maria Grazia ^{[1
,2
,6
]}

Naldini, Luigi ^{[1
]}

机构：

[1] Ist Sci San Raffaele, Div Regenerat Med Stem Cells & Gene Therapy, San Raffaele Telethon Inst Gene Therapy HSR TIGET, I-20132 Milan, Italy

[2] Ist Sci San Raffaele, HSR TIGET Pediat Clin Res Unit, I-20132 Milan, Italy

[3] Ist Sci San Raffaele, Pediat Immunohematol & Bone Marrow Transplant Uni, I-20132 Milan, Italy

[4] Bambino Gesu Pediat Hosp, Univ Dept Pediat DPUO, I-00165 Rome, Italy

[5] Tor Vergata Univ, Sch Med, I-20132 Rome, Italy

[6] Univ Vita Salute San Raffaele, I-20132 Milan, Italy

[7] Ist Sci San Raffaele, Hematol & Bone Marrow Transplant Unit, I-20132 Milan, Italy

[8] MolMed SpA, Milan, Italy

[9] Univ Vita Salute San Raffaele, Univ Ctr Stat Biomed Sci CUSSB, I-20132 Milan, Italy

[10] Deutsch Krebsforschungszentrum, Nat Zentrum Tumorerkrankungen, D-69120 Heidelberg, Germany

[11] GlaxoSmithKline Res & Dev Ltd, Regenerat Med Discovery Performance Unit, King Of Prussia, PA 19406 USA

[12] GlaxoSmithKline, Stevenage SG1 2NY, Herts, England

[13] UMR 951, F-91002 Evry, France

[14] Magna Graecia Univ Catanzaro, Dipartimento Sci Med Chirurg, I-88100 Catanzaro, Italy

[15] Ankara Childrens Hosp, TR-06050 Ankara, Turkey

[16] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA

[17] Univ Milano Bicocca, Dipartimento Med Clin & Prevenzione, I-20126 Monza, Italy

[18] CNR, IRGB, I-20138 Milan, Italy

来源：

SCIENCE | 2013年 / 341卷 / 6148期

关键词：

RETROVIRAL INTEGRATION SITES; SYNDROME PROTEIN; MOUSE MODEL; T-CELLS; VECTOR; TRANSPLANTATION; WASP; IMMUNODEFICIENCIES; EXPRESSION; EFFICACY;

D O I：

10.1126/science.1233151

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：865 / U71

页数：13

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