Gene Therapy mediated by lentiviral vector transduced CD34+ cells for the treatment of Wiskott-Aldrich Syndrome
Samantha
Scaramuzza1,
Francesca
Ferrua2,
Maria
C.
Castiello1, 3,
Stefania
Giannelli1,
Luca
Biasco1,
Fabio
Ciceri4,
Maria Grazia
Roncarolo1, 2, 3,
Anna
Villa1, 5,
Luigi
Naldini1, 3 and
Alessandro
Aiuti1, 2, 6*
-
1
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Italy
-
2
Scientific Institute HS Raffaele, Pediatric Immunology, Italy
-
3
Università Vita-Salute San Raffaele, Italy
-
4
Scientific Institute HS Raffaele, Div. of Hematology, Italy
-
5
IRGB-CNR, Italy
-
6
University of Rome “Tor Vergata”, Italy
Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia, infections, autoimmunity and lymphomas. Gene therapy with ex vivo transduced hematopoietic stem cells could represent a valid therapeutic option to transplantation. We developed an approach based on a lentiviral vector (LV) encoding for WAS under the control of the homologous 1.6 kb WAS promoter. We designed a phase I/II clinical trial based on infusion of autologous transduced CD34+ cells derived from bone marrow (BM) or mobilized peripheral blood (PB) and reduced intensity conditioning. Transduction of clonogenic progenitors was highly efficient (94.4 ± 4.2%), with a mean vector copy number (VCN)/genome in bulk CD34+ cells of 2.7 ± 0.98. In the first 3 treated patients, at the latest follow up, robust multilineage engraftment was observed in BM (VCN in myeloid lineages: 0.36-0.78) including clonogenic progenitors (25.8-48.2%), and in PB cells (VCN range of 0.30-1.30 in myeloid cells). As expected, a selective advantage was observed in lymphoid lineages (VCN: 0.93-2.04 and WASP+ cells: 70.9 ± 4.8%). TCR repertoire, proliferative responses to anti-CD3, and NK cytotoxic ability were improved. WASP expression was also observed in the majority of platelets. All patients are currently clinically well and independent from platelet transfusions.
In conclusion, the unprecedented level of gene transfer obtained with LV-WAS resulted in robust engraftment of transduced HSC even when combined to reduced intensity conditioning. The ongoing follow up will allow to establish the long-term safety and clinical efficacy of LV gene therapy for WAS.
Keywords:
Gene Therapy,
immunodeficiency,
Wiskott-Aldrich Syndrome,
Lentiviral vectors,
HSC
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Translational immunology and immune intervention
Citation:
Scaramuzza
S,
Ferrua
F,
Castiello
MC,
Giannelli
S,
Biasco
L,
Ciceri
F,
Roncarolo
M,
Villa
A,
Naldini
L and
Aiuti
A
(2013). Gene Therapy mediated by lentiviral vector transduced CD34+ cells for the treatment of Wiskott-Aldrich Syndrome.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00403
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Received:
09 Apr 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Prof. Alessandro Aiuti, San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy, alessandro.aiuti@hsr.it