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
Institución: Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador: oai:ri.conicet.gov.ar:11336/84325

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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 Técnicas2025-10-22T12:12:05Zoai: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:34982025-10-22 12:12:06.077CONICET 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
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repository.mail.fl_str_mv	dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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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...

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