Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial

Autores
Ghulam Muhammad, A.K.M.; Xiong, Weidong; Puntel, Mariana; Farrokhi, Catherine; Kroeger, Kurt M.; Salem, Alireza; Lacayo, Liliana; Pechnick, Robert N.; Kelson, Kyle R.; Palmer, Donna; Ng, Philip; Liu, Chunyan; Lowenstein, Pedro R.; Castro, Maria G.
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Adenoviral vectors (Ads) have been evaluated in clinical trials for glioma. However, systemic immunity against the vectors can hamper therapeutic efficacy. We demonstrated that combined immunostimulation and cytotoxic gene therapy provides long-term survival in preclinical glioma models. Because helper-dependent high-capacity Ads (HC-Ads) elicit sustained transgene expression, in the presence of antiadenoviral immunity, we engineered HC-Ads encoding conditional cytotoxic herpes simplex type 1 thymidine kinase and immunostimulatory cytokine Fms-like tyrosine kinase ligand-3 under the control of the TetOn system. Escalating doses of combined HC-Ads (1×10 8, 1×109, and 1×1010 viral particles [VP]) were delivered into the rat brain. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points after vector delivery. Histopathological analysis did not reveal any evidence of toxicity or long-term inflammation at the lower doses tested. Vector genomes were restricted to the injection site. Serum chemistry did not uncover adverse systemic side effects at any of the doses tested. Taken together, our data indicate that doses of up to 1×109 VP of each HC-Ad can be safely administered into the normal brain. This comprehensive toxicity and biodistribution study will lay the foundations for implementation of a phase 1 clinical trial for GBM using HC-Ads.
Fil: Ghulam Muhammad, A.K.M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Xiong, Weidong. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados Unidos
Fil: Puntel, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Farrokhi, Catherine. Cedars Sinai Medical Center; Estados Unidos
Fil: Kroeger, Kurt M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Salem, Alireza. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Lacayo, Liliana. Cedars Sinai Medical Center; Estados Unidos
Fil: Pechnick, Robert N.. Cedars Sinai Medical Center; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Kelson, Kyle R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Palmer, Donna. Baylor College of Medicine; Estados Unidos
Fil: Ng, Philip. Baylor College of Medicine; Estados Unidos
Fil: Liu, Chunyan. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Lowenstein, Pedro R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Castro, Maria G.. University of Michigan; Estados Unidos. University of California at Los Angeles; Estados Unidos. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Materia
GLioblastoma
HC-Ad
HSV-1TK & FLt3L
preclinical study
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:11336/100080
Acceder
id CONICETDig_d095f6898792c90ac9c351a1cd303381
oai_identifier_str oai:ri.conicet.gov.ar:11336/100080
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trialGhulam Muhammad, A.K.M.Xiong, WeidongPuntel, MarianaFarrokhi, CatherineKroeger, Kurt M.Salem, AlirezaLacayo, LilianaPechnick, Robert N.Kelson, Kyle R.Palmer, DonnaNg, PhilipLiu, ChunyanLowenstein, Pedro R.Castro, Maria G.GLioblastomaHC-AdHSV-1TK & FLt3Lpreclinical studyhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Adenoviral vectors (Ads) have been evaluated in clinical trials for glioma. However, systemic immunity against the vectors can hamper therapeutic efficacy. We demonstrated that combined immunostimulation and cytotoxic gene therapy provides long-term survival in preclinical glioma models. Because helper-dependent high-capacity Ads (HC-Ads) elicit sustained transgene expression, in the presence of antiadenoviral immunity, we engineered HC-Ads encoding conditional cytotoxic herpes simplex type 1 thymidine kinase and immunostimulatory cytokine Fms-like tyrosine kinase ligand-3 under the control of the TetOn system. Escalating doses of combined HC-Ads (1×10 8, 1×109, and 1×1010 viral particles [VP]) were delivered into the rat brain. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points after vector delivery. Histopathological analysis did not reveal any evidence of toxicity or long-term inflammation at the lower doses tested. Vector genomes were restricted to the injection site. Serum chemistry did not uncover adverse systemic side effects at any of the doses tested. Taken together, our data indicate that doses of up to 1×109 VP of each HC-Ad can be safely administered into the normal brain. This comprehensive toxicity and biodistribution study will lay the foundations for implementation of a phase 1 clinical trial for GBM using HC-Ads.Fil: Ghulam Muhammad, A.K.M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Xiong, Weidong. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados UnidosFil: Puntel, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Farrokhi, Catherine. Cedars Sinai Medical Center; Estados UnidosFil: Kroeger, Kurt M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Salem, Alireza. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Lacayo, Liliana. Cedars Sinai Medical Center; Estados UnidosFil: Pechnick, Robert N.. Cedars Sinai Medical Center; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Kelson, Kyle R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Palmer, Donna. Baylor College of Medicine; Estados UnidosFil: Ng, Philip. Baylor College of Medicine; Estados UnidosFil: Liu, Chunyan. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosFil: Lowenstein, Pedro R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Castro, Maria G.. University of Michigan; Estados Unidos. University of California at Los Angeles; Estados Unidos. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados UnidosMary Ann Liebert2012-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/100080Ghulam Muhammad, A.K.M.; Xiong, Weidong; Puntel, Mariana; Farrokhi, Catherine; Kroeger, Kurt M.; et al.; Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial; Mary Ann Liebert; Human Gene Therapy Methods; 23; 4; 8-2012; 271-2841946-65361946-6544CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.liebertpub.com/doi/10.1089/hgtb.2012.060info:eu-repo/semantics/altIdentifier/doi/10.1089/hgtb.2012.060info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:32:41Zoai:ri.conicet.gov.ar:11336/100080instacron: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 11:32:41.627CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial
title Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial
spellingShingle Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial
Ghulam Muhammad, A.K.M.
GLioblastoma
HC-Ad
HSV-1TK & FLt3L
preclinical study
title_short Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial
title_full Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial
title_fullStr Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial
title_full_unstemmed Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial
title_sort Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial
dc.creator.none.fl_str_mv Ghulam Muhammad, A.K.M.
Xiong, Weidong
Puntel, Mariana
Farrokhi, Catherine
Kroeger, Kurt M.
Salem, Alireza
Lacayo, Liliana
Pechnick, Robert N.
Kelson, Kyle R.
Palmer, Donna
Ng, Philip
Liu, Chunyan
Lowenstein, Pedro R.
Castro, Maria G.
author Ghulam Muhammad, A.K.M.
author_facet Ghulam Muhammad, A.K.M.
Xiong, Weidong
Puntel, Mariana
Farrokhi, Catherine
Kroeger, Kurt M.
Salem, Alireza
Lacayo, Liliana
Pechnick, Robert N.
Kelson, Kyle R.
Palmer, Donna
Ng, Philip
Liu, Chunyan
Lowenstein, Pedro R.
Castro, Maria G.
author_role author
author2 Xiong, Weidong
Puntel, Mariana
Farrokhi, Catherine
Kroeger, Kurt M.
Salem, Alireza
Lacayo, Liliana
Pechnick, Robert N.
Kelson, Kyle R.
Palmer, Donna
Ng, Philip
Liu, Chunyan
Lowenstein, Pedro R.
Castro, Maria G.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv GLioblastoma
HC-Ad
HSV-1TK & FLt3L
preclinical study
topic GLioblastoma
HC-Ad
HSV-1TK & FLt3L
preclinical study
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Adenoviral vectors (Ads) have been evaluated in clinical trials for glioma. However, systemic immunity against the vectors can hamper therapeutic efficacy. We demonstrated that combined immunostimulation and cytotoxic gene therapy provides long-term survival in preclinical glioma models. Because helper-dependent high-capacity Ads (HC-Ads) elicit sustained transgene expression, in the presence of antiadenoviral immunity, we engineered HC-Ads encoding conditional cytotoxic herpes simplex type 1 thymidine kinase and immunostimulatory cytokine Fms-like tyrosine kinase ligand-3 under the control of the TetOn system. Escalating doses of combined HC-Ads (1×10 8, 1×109, and 1×1010 viral particles [VP]) were delivered into the rat brain. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points after vector delivery. Histopathological analysis did not reveal any evidence of toxicity or long-term inflammation at the lower doses tested. Vector genomes were restricted to the injection site. Serum chemistry did not uncover adverse systemic side effects at any of the doses tested. Taken together, our data indicate that doses of up to 1×109 VP of each HC-Ad can be safely administered into the normal brain. This comprehensive toxicity and biodistribution study will lay the foundations for implementation of a phase 1 clinical trial for GBM using HC-Ads.
Fil: Ghulam Muhammad, A.K.M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Xiong, Weidong. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados Unidos
Fil: Puntel, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Farrokhi, Catherine. Cedars Sinai Medical Center; Estados Unidos
Fil: Kroeger, Kurt M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Salem, Alireza. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Lacayo, Liliana. Cedars Sinai Medical Center; Estados Unidos
Fil: Pechnick, Robert N.. Cedars Sinai Medical Center; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Kelson, Kyle R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Palmer, Donna. Baylor College of Medicine; Estados Unidos
Fil: Ng, Philip. Baylor College of Medicine; Estados Unidos
Fil: Liu, Chunyan. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
Fil: Lowenstein, Pedro R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados Unidos. University of California at Los Angeles; Estados Unidos
Fil: Castro, Maria G.. University of Michigan; Estados Unidos. University of California at Los Angeles; Estados Unidos. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos
description Adenoviral vectors (Ads) have been evaluated in clinical trials for glioma. However, systemic immunity against the vectors can hamper therapeutic efficacy. We demonstrated that combined immunostimulation and cytotoxic gene therapy provides long-term survival in preclinical glioma models. Because helper-dependent high-capacity Ads (HC-Ads) elicit sustained transgene expression, in the presence of antiadenoviral immunity, we engineered HC-Ads encoding conditional cytotoxic herpes simplex type 1 thymidine kinase and immunostimulatory cytokine Fms-like tyrosine kinase ligand-3 under the control of the TetOn system. Escalating doses of combined HC-Ads (1×10 8, 1×109, and 1×1010 viral particles [VP]) were delivered into the rat brain. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points after vector delivery. Histopathological analysis did not reveal any evidence of toxicity or long-term inflammation at the lower doses tested. Vector genomes were restricted to the injection site. Serum chemistry did not uncover adverse systemic side effects at any of the doses tested. Taken together, our data indicate that doses of up to 1×109 VP of each HC-Ad can be safely administered into the normal brain. This comprehensive toxicity and biodistribution study will lay the foundations for implementation of a phase 1 clinical trial for GBM using HC-Ads.
publishDate 2012
dc.date.none.fl_str_mv 2012-08
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/11336/100080
Ghulam Muhammad, A.K.M.; Xiong, Weidong; Puntel, Mariana; Farrokhi, Catherine; Kroeger, Kurt M.; et al.; Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial; Mary Ann Liebert; Human Gene Therapy Methods; 23; 4; 8-2012; 271-284
1946-6536
1946-6544
CONICET Digital
CONICET
url http://hdl.handle.net/11336/100080
identifier_str_mv Ghulam Muhammad, A.K.M.; Xiong, Weidong; Puntel, Mariana; Farrokhi, Catherine; Kroeger, Kurt M.; et al.; Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: Implications for a glioma phase 1 clinical trial; Mary Ann Liebert; Human Gene Therapy Methods; 23; 4; 8-2012; 271-284
1946-6536
1946-6544
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://www.liebertpub.com/doi/10.1089/hgtb.2012.060
info:eu-repo/semantics/altIdentifier/doi/10.1089/hgtb.2012.060
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 Mary Ann Liebert
publisher.none.fl_str_mv Mary Ann Liebert
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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score 12.982451

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