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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/100080
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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 Técnicas2025-09-29T10:03:03Zoai: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:34982025-09-29 10:03:03.915CONICET 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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1844613841705500672 |
score |
13.070432 |