Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a ph...

Autores
Puntel, Mariana; Ghulam Muhammad, A. K. M.; Farrokhi, Catherine; VanderVeen, Nathan; Paran, Christopher; Appelhans, Ashley; Kroeger, Kurt M.; Salem, Alireza; Lacayo, Liliana; Pechnick, Robert N.; Kelson, Kyle R.; Kaur, Sukhpreet; Kennedy, Sean; Palmer, Donna; Ng, Philip; Liu, Chunyan; Krasinkiewicz, Johnny; Lowenstein, Pedro R.; Castro, Maria G.
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L).Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression "on" or "off" according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1×108, 1×109, or 1×1010 viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1×109 vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and underpin further developments for its implementation in a phase I clinical trial for glioma.
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. University of Michigan. School of Medicine; España. Cedars Sinai Medical Center; Estados Unidos
Fil: Ghulam Muhammad, A. K. M.. Cedars Sinai Medical Center; Estados Unidos
Fil: Farrokhi, Catherine. Cedars Sinai Medical Center; Estados Unidos
Fil: VanderVeen, Nathan. University of Michigan. School of Medicine; España
Fil: Paran, Christopher. University of Michigan. School of Medicine; España
Fil: Appelhans, Ashley. University of Michigan. School of Medicine; España
Fil: Kroeger, Kurt M.. Cedars Sinai Medical Center; Estados Unidos
Fil: Salem, Alireza. Cedars Sinai Medical Center; Estados Unidos
Fil: Lacayo, Liliana. Cedars Sinai Medical Center; Estados Unidos
Fil: Pechnick, Robert N.. University of California at Los Angeles; Estados Unidos
Fil: Kelson, Kyle R.. Cedars Sinai Medical Center; Estados Unidos
Fil: Kaur, Sukhpreet. Cedars Sinai Medical Center; Estados Unidos
Fil: Kennedy, Sean. Cedars Sinai Medical Center; 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; Estados Unidos
Fil: Krasinkiewicz, Johnny. University of Michigan. School of Medicine; España
Fil: Lowenstein, Pedro R.. Cedars Sinai Medical Center; Estados Unidos. University of Michigan. School of Medicine; España. University of California at Los Angeles; Estados Unidos
Fil: Castro, Maria G.. Cedars Sinai Medical Center; Estados Unidos. University of Michigan. School of Medicine; España. University of California at Los Angeles; Estados Unidos
Materia
BICISTRONIC HC-AD
BIODISTRIBUTION
EFFICACY
GLIOBLASTOMA
NEUROPATHOLOGY
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:11336/84325

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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastomaPuntel, MarianaGhulam Muhammad, A. K. M.Farrokhi, CatherineVanderVeen, NathanParan, ChristopherAppelhans, AshleyKroeger, Kurt M.Salem, AlirezaLacayo, LilianaPechnick, Robert N.Kelson, Kyle R.Kaur, SukhpreetKennedy, SeanPalmer, DonnaNg, PhilipLiu, ChunyanKrasinkiewicz, JohnnyLowenstein, Pedro R.Castro, Maria G.BICISTRONIC HC-ADBIODISTRIBUTIONEFFICACYGLIOBLASTOMANEUROPATHOLOGYhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L).Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression "on" or "off" according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1×108, 1×109, or 1×1010 viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1×109 vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and underpin further developments for its implementation in a phase I clinical trial for glioma.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. University of Michigan. School of Medicine; España. Cedars Sinai Medical Center; Estados UnidosFil: Ghulam Muhammad, A. K. M.. Cedars Sinai Medical Center; Estados UnidosFil: Farrokhi, Catherine. Cedars Sinai Medical Center; Estados UnidosFil: VanderVeen, Nathan. University of Michigan. School of Medicine; EspañaFil: Paran, Christopher. University of Michigan. School of Medicine; EspañaFil: Appelhans, Ashley. University of Michigan. School of Medicine; EspañaFil: Kroeger, Kurt M.. Cedars Sinai Medical Center; Estados UnidosFil: Salem, Alireza. Cedars Sinai Medical Center; Estados UnidosFil: Lacayo, Liliana. Cedars Sinai Medical Center; Estados UnidosFil: Pechnick, Robert N.. University of California at Los Angeles; Estados UnidosFil: Kelson, Kyle R.. Cedars Sinai Medical Center; Estados UnidosFil: Kaur, Sukhpreet. Cedars Sinai Medical Center; Estados UnidosFil: Kennedy, Sean. Cedars Sinai Medical Center; Estados UnidosFil: Palmer, Donna. Baylor College of Medicine; Estados UnidosFil: Ng, Philip. Baylor College of Medicine; Estados UnidosFil: Liu, Chunyan. Cedars Sinai Medical Center; Estados UnidosFil: Krasinkiewicz, Johnny. University of Michigan. School of Medicine; EspañaFil: Lowenstein, Pedro R.. Cedars Sinai Medical Center; Estados Unidos. University of Michigan. School of Medicine; España. University of California at Los Angeles; Estados UnidosFil: Castro, Maria G.. Cedars Sinai Medical Center; Estados Unidos. University of Michigan. School of Medicine; España. University of California at Los Angeles; Estados UnidosAcademic Press Inc Elsevier Science2013-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/84325Puntel, Mariana; Ghulam Muhammad, A. K. M.; Farrokhi, Catherine; VanderVeen, Nathan; Paran, Christopher; et al.; Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma; Academic Press Inc Elsevier Science; Toxicology and Applied Pharmacology; 268; 3; 5-2013; 318-3300041-008XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.taap.2013.02.001info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0041008X13000562info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:39:45Zoai:ri.conicet.gov.ar:11336/84325instacron: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 10:39:45.794CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma
title Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma
spellingShingle Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma
Puntel, Mariana
BICISTRONIC HC-AD
BIODISTRIBUTION
EFFICACY
GLIOBLASTOMA
NEUROPATHOLOGY
title_short Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma
title_full Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma
title_fullStr Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma
title_full_unstemmed Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma
title_sort Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma
dc.creator.none.fl_str_mv Puntel, Mariana
Ghulam Muhammad, A. K. M.
Farrokhi, Catherine
VanderVeen, Nathan
Paran, Christopher
Appelhans, Ashley
Kroeger, Kurt M.
Salem, Alireza
Lacayo, Liliana
Pechnick, Robert N.
Kelson, Kyle R.
Kaur, Sukhpreet
Kennedy, Sean
Palmer, Donna
Ng, Philip
Liu, Chunyan
Krasinkiewicz, Johnny
Lowenstein, Pedro R.
Castro, Maria G.
author Puntel, Mariana
author_facet Puntel, Mariana
Ghulam Muhammad, A. K. M.
Farrokhi, Catherine
VanderVeen, Nathan
Paran, Christopher
Appelhans, Ashley
Kroeger, Kurt M.
Salem, Alireza
Lacayo, Liliana
Pechnick, Robert N.
Kelson, Kyle R.
Kaur, Sukhpreet
Kennedy, Sean
Palmer, Donna
Ng, Philip
Liu, Chunyan
Krasinkiewicz, Johnny
Lowenstein, Pedro R.
Castro, Maria G.
author_role author
author2 Ghulam Muhammad, A. K. M.
Farrokhi, Catherine
VanderVeen, Nathan
Paran, Christopher
Appelhans, Ashley
Kroeger, Kurt M.
Salem, Alireza
Lacayo, Liliana
Pechnick, Robert N.
Kelson, Kyle R.
Kaur, Sukhpreet
Kennedy, Sean
Palmer, Donna
Ng, Philip
Liu, Chunyan
Krasinkiewicz, Johnny
Lowenstein, Pedro R.
Castro, Maria G.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv BICISTRONIC HC-AD
BIODISTRIBUTION
EFFICACY
GLIOBLASTOMA
NEUROPATHOLOGY
topic BICISTRONIC HC-AD
BIODISTRIBUTION
EFFICACY
GLIOBLASTOMA
NEUROPATHOLOGY
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) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L).Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression "on" or "off" according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1×108, 1×109, or 1×1010 viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1×109 vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and underpin further developments for its implementation in a phase I clinical trial for glioma.
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. University of Michigan. School of Medicine; España. Cedars Sinai Medical Center; Estados Unidos
Fil: Ghulam Muhammad, A. K. M.. Cedars Sinai Medical Center; Estados Unidos
Fil: Farrokhi, Catherine. Cedars Sinai Medical Center; Estados Unidos
Fil: VanderVeen, Nathan. University of Michigan. School of Medicine; España
Fil: Paran, Christopher. University of Michigan. School of Medicine; España
Fil: Appelhans, Ashley. University of Michigan. School of Medicine; España
Fil: Kroeger, Kurt M.. Cedars Sinai Medical Center; Estados Unidos
Fil: Salem, Alireza. Cedars Sinai Medical Center; Estados Unidos
Fil: Lacayo, Liliana. Cedars Sinai Medical Center; Estados Unidos
Fil: Pechnick, Robert N.. University of California at Los Angeles; Estados Unidos
Fil: Kelson, Kyle R.. Cedars Sinai Medical Center; Estados Unidos
Fil: Kaur, Sukhpreet. Cedars Sinai Medical Center; Estados Unidos
Fil: Kennedy, Sean. Cedars Sinai Medical Center; 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; Estados Unidos
Fil: Krasinkiewicz, Johnny. University of Michigan. School of Medicine; España
Fil: Lowenstein, Pedro R.. Cedars Sinai Medical Center; Estados Unidos. University of Michigan. School of Medicine; España. University of California at Los Angeles; Estados Unidos
Fil: Castro, Maria G.. Cedars Sinai Medical Center; Estados Unidos. University of Michigan. School of Medicine; España. University of California at Los Angeles; Estados Unidos
description Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L).Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression "on" or "off" according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1×108, 1×109, or 1×1010 viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1×109 vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and underpin further developments for its implementation in a phase I clinical trial for glioma.
publishDate 2013
dc.date.none.fl_str_mv 2013-05
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/11336/84325
Puntel, Mariana; Ghulam Muhammad, A. K. M.; Farrokhi, Catherine; VanderVeen, Nathan; Paran, Christopher; et al.; Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma; Academic Press Inc Elsevier Science; Toxicology and Applied Pharmacology; 268; 3; 5-2013; 318-330
0041-008X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/84325
identifier_str_mv Puntel, Mariana; Ghulam Muhammad, A. K. M.; Farrokhi, Catherine; VanderVeen, Nathan; Paran, Christopher; et al.; Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma; Academic Press Inc Elsevier Science; Toxicology and Applied Pharmacology; 268; 3; 5-2013; 318-330
0041-008X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.taap.2013.02.001
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0041008X13000562
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 Academic Press Inc Elsevier Science
publisher.none.fl_str_mv Academic Press Inc Elsevier Science
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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