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
Ver los metadatos del registro completo
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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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1844614423694540800 |
score |
13.070432 |