Evidence for long-term efficacy and safety of gene therapy for Wiskott-Aldrich syndrome in preclinical models.
Wiskott-Aldrich Syndrome (WAS) is a life-threatening X-linked disease characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancies. Gene therapy could represent a therapeutic option for patients lacking a suitable bone marrow (BM) donor. In this study, we analyzed the long-term outcome of WAS gene therapy mediated by a clinically compatible lentiviral vector (LV) in a large cohort of was(null) mice. We demonstrated stable and full donor engraftment and Wiskott-Aldrich Syndrome protein (WASP) expression in various hematopoietic lineages, up to 12 months after gene therapy. Importantly, we observed a selective advantage for T and B lymphocytes expressing transgenic WASP. T-cell receptor (TCR)-driven T-cell activation, as well as B-cell's ability to migrate in response to CXCL13, was fully restored. Safety was evaluated throughout the long-term follow-up of primary and secondary recipients of WAS gene therapy. WAS gene therapy did not affect the lifespan of treated animals. Both hematopoietic and nonhematopoietic tumors arose, but we excluded the association with gene therapy in all cases. Demonstration of long-term efficacy and safety of WAS gene therapy mediated by a clinically applicable LV is a key step toward the implementation of a gene therapy clinical trial for WAS.
Marangoni
Francesco
F
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
Bosticardo
Marita
M
Charrier
Sabine
S
Draghici
Elena
E
Locci
Michela
M
Scaramuzza
Samantha
S
Panaroni
Cristina
C
Ponzoni
Maurilio
M
Sanvito
Francesca
F
Doglioni
Claudio
C
Liabeuf
Marie
M
Gjata
Bernard
B
Montus
Marie
M
Siminovitch
Katherine
K
Aiuti
Alessandro
A
Naldini
Luigi
L
Dupré
Loïc
L
Roncarolo
Maria Grazia
MG
Galy
Anne
A
Villa
Anna
A
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods*; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D014923:Wiskott-Aldrich Syndrome / Q000378:metabolism / Q000628:therapy*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism
D051316:Wiskott-Aldrich Syndrome Protein