INVESTIGADORES
DEWEY Ricardo Alfredo
artículos
Título:
Development of novel efficient SIN vectors with improved safety features for Wiskott Aldrich Syndrome stem cell based gene therapy
Autor/es:
I. AVEDILLO DÍEZ; D. ZYCHLINSKI; R. A. DEWEY; M. GALLA; U. MODLICH; K. BOZTUG; C. BAUM; C. KLEIN; A. SCHAMBACH
Revista:
MOLECULAR PHARMACEUTICS
Editorial:
AMER CHEMICAL SOC
Referencias:
Año: 2011 vol. 8 p. 1525 - 1537
ISSN:
1543-8384
Resumen:
Gene therapy has proven as a promising therapeutic approach to treat primary
immunodeficiencies. Indeed, the clinical trial for the Wiskott-Aldrich Syndrome (WAS) that is
currently ongoing at the Hannover Medical School (Germany) has recently reported the
correction of all affected cell lineages of the hematopoietic system in the first treated patients.
However, an extensive study of the clonal inventory of those patients reveals that LMO2,
CCND2 and MDS1/EVI1 were targeted preferentially. Moreover, a first leukemia case was
observed, thus reinforcing the need of developing safer vectors for gene transfer into HSC.
Here we present a novel self-inactivating (SIN) vector for the gene therapy of WAS
that combines improved safety features. We used the elongation factor 1 alpha (EFS)
promoter, which has been extensively evaluated in terms of safety profile, to drive a codon-
optimized human WASP cDNA. To test vector performance in a clinically relevant setting, we
transduced murine HSPC as well as human CD34+ cells and also tested vector performance
in their differentiated myeloid progeny. Our results show that our novel vector is as effective
as the clinically used LTR-driven vector. Therefore, the described SIN vectors appear to be
good candidates for potential use in a safer new gene therapy protocol for WAS, with
decreased risk of insertional mutagenesis.