Gene Therapy for Wiskott-Aldrich Syndrome-Long-Term Efficacy and Genotoxicity

被引：416

作者：

Braun, Christian Joerg ^{[1
]}

Boztug, Kaan ^{[2
]}

Paruzynski, Anna ^{[3
,4
]}

Witzel, Maximilian ^{[1
]}

Schwarzer, Adrian ^{[2
,5
]}

Rothe, Michael ^{[5
]}

Modlich, Ute ^{[5
]}

Beier, Rita ^{[2
]}

Goehring, Gudrun ^{[6
]}

Steinemann, Doris ^{[6
]}

Fronza, Raffaele ^{[3
,4
]}

Ball, Claudia Regina ^{[3
,4
,7
]}

Haemmerle, Reinhard ^{[5
]}

Naundorf, Sonja ^{[8
]}

Kuelcke, Klaus ^{[8
]}

Rose, Martina ^{[9
]}

Fraser, Chris ^{[10
]}

Mathias, Liesl ^{[11
]}

Ferrari, Rudolf ^{[12
]}

Abboud, Miguel R. ^{[13
]}

Al-Herz, Waleed ^{[14
]}

Kondratenko, Irina ^{[15
]}

Marodi, Laszlo ^{[16
]}

Glimm, Hanno ^{[3
,4
,7
]}

Schlegelberger, Brigitte ^{[6
]}

Schambach, Axel ^{[5
]}

Albert, Michael Heinrich ^{[1
]}

Schmidt, Manfred ^{[3
,4
]}

von Kalle, Christof ^{[3
,4
,7
]}

Klein, Christoph ^{[1
]}

机构：

[1] Univ Munich, Dr von Hauner Childrens Hosp, D-80337 Munich, Germany

[2] Hannover Med Sch, Dept Pediat Hematol Oncol, D-30625 Hannover, Germany

[3] Natl Ctr Tumor Dis, Dept Translat Oncol, D-69120 Heidelberg, Germany

[4] German Canc Res Ctr, D-69120 Heidelberg, Germany

[5] Hannover Med Sch, Inst Expt Hematol, D-30625 Hannover, Germany

[6] Hannover Med Sch, Inst Cell & Mol Pathol, D-30625 Hannover, Germany

[7] German Canc Consortium, Berlin, Germany

[8] EUFETS AG, D-55743 Idar Oberstein, Germany

[9] Minden Hosp, Dept Pediat, D-32429 Minden, Germany

[10] Royal Childrens Hosp, Queensland Childrens Canc Ctr, Brisbane, Qld 4006, Australia

[11] Loma Linda Univ, Med Ctr, Dept Pediat Hematol & Oncol, Loma Linda, CA 92354 USA

[12] Childrens Hosp Kemperhof, D-56073 Koblenz, Germany

[13] Amer Univ Beirut, Med Ctr, Dept Pediat & Adolescent Med, Beirut 11072020, Lebanon

[14] Kuwait Univ, Fac Med, Dept Pediat, Kuwait, Kuwait

[15] Russian Clin Childrens Hosp, Dept Clin Immunol, Moscow 117513, Russia

[16] Univ Debrecen, Dept Infect & Pediat Immunol, Med & Hlth Sci Ctr, H-4032 Debrecen, Hungary

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2014年 / 6卷 / 227期

关键词：

SEVERE COMBINED IMMUNODEFICIENCY; CELL REPERTOIRE DIVERSITY; T-CELL; INSERTIONAL MUTAGENESIS; VECTOR INTEGRATION; SCID-X1; ACTIVATION; MUTATIONS; SUBSETS; ACTIN;

D O I：

10.1126/scitranslmed.3007280

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a g-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed > 140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of g-retroviral vectors is associated with a substantial risk of leukemogenesis.

引用

页数：14

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