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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/95264
Acceder
id CONICETDig_0cff95956ad3c7161e8e0d5d098c541f
oai_identifier_str oai:ri.conicet.gov.ar:11336/95264
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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 Técnicas2025-10-22T11:25:34Zoai: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:34982025-10-22 11:25:35.063CONICET 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
_version_ 1846781805969014784
score 12.982451

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