Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy
- Autores
- Avedillo Diez, Ines; Zychlinski, Daniela; Coci, Emanuele G.; Galla, Melanie; Modlich, Ute; Dewey, Ricardo; Schwarzer, Adrian; Maetzig, Tobias; Mpofu, Nonsikelelo; Jaeckel, Elmar; Boztug, Kaan; Baum, Christopher; Klein, Christoph; Schambach, Axel
- Año de publicación
- 2011
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Gene therapy is 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 preferentially prevalent. Moreover, a first leukemia case was observed in this study, thus reinforcing the need of developing safer vectors for gene transfer into HSC in general. 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 more clinically relevant setting, we transduced murine HSPC as well as human CD34+ cells and also analyzed vector efficacy in their differentiated myeloid progeny. Our results show that our novel vector generates comparable WAS protein levels and 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.
Fil: Avedillo Diez, Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina. Hannover Medical School; Alemania
Fil: Zychlinski, Daniela. Hannover Medical School; Alemania
Fil: Coci, Emanuele G.. Hannover Medical School; Alemania
Fil: Galla, Melanie. Hannover Medical School; Alemania
Fil: Modlich, Ute. Hannover Medical School; Alemania
Fil: Dewey, Ricardo. Hannover Medical School; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Schwarzer, Adrian. Hannover Medical School; Alemania
Fil: Maetzig, Tobias. Hannover Medical School; Alemania
Fil: Mpofu, Nonsikelelo. Hannover Medical School; Alemania
Fil: Jaeckel, Elmar. Hannover Medical School; Alemania
Fil: Boztug, Kaan. Hannover Medical School; Alemania
Fil: Baum, Christopher. Hannover Medical School; Alemania
Fil: Klein, Christoph. Hannover Medical School; Alemania
Fil: Schambach, Axel. Hannover Medical School; Alemania - Materia
-
retroviral vectors
codon optimization
WAS
gene therapy - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/95264
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oai:ri.conicet.gov.ar:11336/95264 |
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CONICET Digital (CONICET) |
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Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene TherapyAvedillo Diez, InesZychlinski, DanielaCoci, Emanuele G.Galla, MelanieModlich, UteDewey, RicardoSchwarzer, AdrianMaetzig, TobiasMpofu, NonsikeleloJaeckel, ElmarBoztug, KaanBaum, ChristopherKlein, ChristophSchambach, Axelretroviral vectorscodon optimizationWASgene therapyhttps://purl.org/becyt/ford/3.4https://purl.org/becyt/ford/3Gene therapy is 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 preferentially prevalent. Moreover, a first leukemia case was observed in this study, thus reinforcing the need of developing safer vectors for gene transfer into HSC in general. 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 more clinically relevant setting, we transduced murine HSPC as well as human CD34+ cells and also analyzed vector efficacy in their differentiated myeloid progeny. Our results show that our novel vector generates comparable WAS protein levels and 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.Fil: Avedillo Diez, Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina. Hannover Medical School; AlemaniaFil: Zychlinski, Daniela. Hannover Medical School; AlemaniaFil: Coci, Emanuele G.. Hannover Medical School; AlemaniaFil: Galla, Melanie. Hannover Medical School; AlemaniaFil: Modlich, Ute. Hannover Medical School; AlemaniaFil: Dewey, Ricardo. Hannover Medical School; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Schwarzer, Adrian. Hannover Medical School; AlemaniaFil: Maetzig, Tobias. Hannover Medical School; AlemaniaFil: Mpofu, Nonsikelelo. Hannover Medical School; AlemaniaFil: Jaeckel, Elmar. Hannover Medical School; AlemaniaFil: Boztug, Kaan. Hannover Medical School; AlemaniaFil: Baum, Christopher. Hannover Medical School; AlemaniaFil: Klein, Christoph. Hannover Medical School; AlemaniaFil: Schambach, Axel. Hannover Medical School; AlemaniaAmerican Chemical Society2011-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/95264Avedillo Diez, Ines; Zychlinski, Daniela; Coci, Emanuele G.; Galla, Melanie; Modlich, Ute; et al.; Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy; American Chemical Society; Molecular Pharmaceutics; 8; 5; 10-2011; 1525-15371543-8384CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/mp200132uinfo:eu-repo/semantics/altIdentifier/doi/10.1021/mp200132uinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:56:24Zoai:ri.conicet.gov.ar:11336/95264instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:56:24.402CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy |
title |
Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy |
spellingShingle |
Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy Avedillo Diez, Ines retroviral vectors codon optimization WAS gene therapy |
title_short |
Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy |
title_full |
Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy |
title_fullStr |
Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy |
title_full_unstemmed |
Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy |
title_sort |
Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy |
dc.creator.none.fl_str_mv |
Avedillo Diez, Ines Zychlinski, Daniela Coci, Emanuele G. Galla, Melanie Modlich, Ute Dewey, Ricardo Schwarzer, Adrian Maetzig, Tobias Mpofu, Nonsikelelo Jaeckel, Elmar Boztug, Kaan Baum, Christopher Klein, Christoph Schambach, Axel |
author |
Avedillo Diez, Ines |
author_facet |
Avedillo Diez, Ines Zychlinski, Daniela Coci, Emanuele G. Galla, Melanie Modlich, Ute Dewey, Ricardo Schwarzer, Adrian Maetzig, Tobias Mpofu, Nonsikelelo Jaeckel, Elmar Boztug, Kaan Baum, Christopher Klein, Christoph Schambach, Axel |
author_role |
author |
author2 |
Zychlinski, Daniela Coci, Emanuele G. Galla, Melanie Modlich, Ute Dewey, Ricardo Schwarzer, Adrian Maetzig, Tobias Mpofu, Nonsikelelo Jaeckel, Elmar Boztug, Kaan Baum, Christopher Klein, Christoph Schambach, Axel |
author2_role |
author author author author author author author author author author author author author |
dc.subject.none.fl_str_mv |
retroviral vectors codon optimization WAS gene therapy |
topic |
retroviral vectors codon optimization WAS gene therapy |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.4 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
Gene therapy is 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 preferentially prevalent. Moreover, a first leukemia case was observed in this study, thus reinforcing the need of developing safer vectors for gene transfer into HSC in general. 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 more clinically relevant setting, we transduced murine HSPC as well as human CD34+ cells and also analyzed vector efficacy in their differentiated myeloid progeny. Our results show that our novel vector generates comparable WAS protein levels and 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. Fil: Avedillo Diez, Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina. Hannover Medical School; Alemania Fil: Zychlinski, Daniela. Hannover Medical School; Alemania Fil: Coci, Emanuele G.. Hannover Medical School; Alemania Fil: Galla, Melanie. Hannover Medical School; Alemania Fil: Modlich, Ute. Hannover Medical School; Alemania Fil: Dewey, Ricardo. Hannover Medical School; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina Fil: Schwarzer, Adrian. Hannover Medical School; Alemania Fil: Maetzig, Tobias. Hannover Medical School; Alemania Fil: Mpofu, Nonsikelelo. Hannover Medical School; Alemania Fil: Jaeckel, Elmar. Hannover Medical School; Alemania Fil: Boztug, Kaan. Hannover Medical School; Alemania Fil: Baum, Christopher. Hannover Medical School; Alemania Fil: Klein, Christoph. Hannover Medical School; Alemania Fil: Schambach, Axel. Hannover Medical School; Alemania |
description |
Gene therapy is 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 preferentially prevalent. Moreover, a first leukemia case was observed in this study, thus reinforcing the need of developing safer vectors for gene transfer into HSC in general. 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 more clinically relevant setting, we transduced murine HSPC as well as human CD34+ cells and also analyzed vector efficacy in their differentiated myeloid progeny. Our results show that our novel vector generates comparable WAS protein levels and 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. |
publishDate |
2011 |
dc.date.none.fl_str_mv |
2011-10 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/95264 Avedillo Diez, Ines; Zychlinski, Daniela; Coci, Emanuele G.; Galla, Melanie; Modlich, Ute; et al.; Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy; American Chemical Society; Molecular Pharmaceutics; 8; 5; 10-2011; 1525-1537 1543-8384 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/95264 |
identifier_str_mv |
Avedillo Diez, Ines; Zychlinski, Daniela; Coci, Emanuele G.; Galla, Melanie; Modlich, Ute; et al.; Development of Novel Efficient SIN Vectors with Improved Safety Features for Wiskott–Aldrich Syndrome Stem Cell Based Gene Therapy; American Chemical Society; Molecular Pharmaceutics; 8; 5; 10-2011; 1525-1537 1543-8384 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/mp200132u info:eu-repo/semantics/altIdentifier/doi/10.1021/mp200132u |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
American Chemical Society |
publisher.none.fl_str_mv |
American Chemical Society |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844613694413078528 |
score |
13.070432 |