Specific gene delivery to liver sinusoidal & artery endothelial cells

Tobias Abel; Ebtisam El Filali; Johan Waern; Irene C. Schneider; Qinggong Yuan; Robert C. Münch; Meike Hick; Gregor Warnecke; Nodir Madrahimov; Roland E. Kontermann; Jörg Schuttrumpf; Ulrike C. Müller; Jurgen Seppen; Michael Ott; Christian J. Buchholz

doi:https://doi.org/10.1182/blood-2012-11-468579

Specific gene delivery to liver sinusoidal & artery endothelial cells

Tobias Abel, Ebtisam El Filali, Johan Waern, Irene C. Schneider, Qinggong Yuan, Robert C. Münch, Meike Hick, Gregor Warnecke, Nodir Madrahimov, Roland E. Kontermann, Jörg Schuttrumpf, Ulrike C. Müller, Jurgen Seppen, Michael Ott, Christian J. Buchholz

Research output: Contribution to journal › Article › Academic › peer-review

41 Citations (Scopus)

Abstract

Different types of endothelial cells (EC) fulfill distinct tasks depending on their microenvironment. ECs are therefore difficult to genetically manipulate ex vivo for functional studies or gene therapy. We assessed lentiviral vectors (LVs) targeted to the EC surface marker CD105 for in vivo gene delivery. The mouse CD105-specific vector, mCD105-LV, transduced only CD105-positive cells in primary liver cell cultures. Upon systemic injection, strong reporter gene expression was detected in liver where mCD105-LV specifically transduced liver sinusoidal ECs (LSECs) but not Kupffer cells, which were mainly transduced by nontargeted LVs. Tumor ECs were specifically targeted upon intratumoral vector injection. Delivery of the erythropoietin gene withmCD105-LV resulted in substantially increased erythropoietin and hematocrit levels. The human CD105-specific vector (huCD105-LV) transduced exclusively human LSECs in mice transplanted with human liver ECs. Interestingly, when applied at higher dose and in absence of target cells in the liver, huCD105-LV transduced ECs of a human artery transplanted into the descending mouse aorta. The data demonstrate for the first time targeted gene delivery to specialized ECs upon systemic vector administration. This strategy offers novel options to better understand the physiological functions of ECs and to treat genetic diseases such as those affecting blood factors. (Blood. 2013;122(12):2030-2038).

Original language	English
Pages (from-to)	2030-2038
Number of pages	9
Journal	Blood
Volume	122
Issue number	12
DOIs	https://doi.org/10.1182/blood-2012-11-468579
Publication status	Published - 2013

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@article{67942b4a71a747498de6f310f7cf4f0d,

title = "Specific gene delivery to liver sinusoidal & artery endothelial cells",

abstract = "Different types of endothelial cells (EC) fulfill distinct tasks depending on their microenvironment. ECs are therefore difficult to genetically manipulate ex vivo for functional studies or gene therapy. We assessed lentiviral vectors (LVs) targeted to the EC surface marker CD105 for in vivo gene delivery. The mouse CD105-specific vector, mCD105-LV, transduced only CD105-positive cells in primary liver cell cultures. Upon systemic injection, strong reporter gene expression was detected in liver where mCD105-LV specifically transduced liver sinusoidal ECs (LSECs) but not Kupffer cells, which were mainly transduced by nontargeted LVs. Tumor ECs were specifically targeted upon intratumoral vector injection. Delivery of the erythropoietin gene withmCD105-LV resulted in substantially increased erythropoietin and hematocrit levels. The human CD105-specific vector (huCD105-LV) transduced exclusively human LSECs in mice transplanted with human liver ECs. Interestingly, when applied at higher dose and in absence of target cells in the liver, huCD105-LV transduced ECs of a human artery transplanted into the descending mouse aorta. The data demonstrate for the first time targeted gene delivery to specialized ECs upon systemic vector administration. This strategy offers novel options to better understand the physiological functions of ECs and to treat genetic diseases such as those affecting blood factors. (Blood. 2013;122(12):2030-2038).",

author = "Tobias Abel and Filali, {Ebtisam El} and Johan Waern and Schneider, {Irene C.} and Qinggong Yuan and M{\"u}nch, {Robert C.} and Meike Hick and Gregor Warnecke and Nodir Madrahimov and Kontermann, {Roland E.} and J{\"o}rg Schuttrumpf and M{\"u}ller, {Ulrike C.} and Jurgen Seppen and Michael Ott and Buchholz, {Christian J.}",

note = "Funding Information: T.A. was supported by the DFG-funded Graduate School (GRK1172). This work was supported by grants from the 7th European Community program project “Persist” and by the LOEWE Center for Cell and Gene Therapy Frankfurt, funded by Hessian Ministry of Funding Information: T.A. was supported by the DFG-funded Graduate School (GRK1172). This work was supported by grants from the 7th European Community program project Persist and by the LOEWE Center for Cell and Gene Therapy Frankfurt, funded by Hessian Ministry of Higher Education, Research, and the Arts (III L 4- 518/17.004 [2010]) to C.J.B. M.O. and G.W. were supported by the Deutsche Forschungsgemeinschaft (SFB 738). Publisher Copyright: {\textcopyright}2013 by The American Society of Hematology. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",

year = "2013",

doi = "https://doi.org/10.1182/blood-2012-11-468579",

language = "English",

volume = "122",

pages = "2030--2038",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "12",

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TY - JOUR

T1 - Specific gene delivery to liver sinusoidal & artery endothelial cells

AU - Abel, Tobias

AU - Filali, Ebtisam El

AU - Waern, Johan

AU - Schneider, Irene C.

AU - Yuan, Qinggong

AU - Münch, Robert C.

AU - Hick, Meike

AU - Warnecke, Gregor

AU - Madrahimov, Nodir

AU - Kontermann, Roland E.

AU - Schuttrumpf, Jörg

AU - Müller, Ulrike C.

AU - Seppen, Jurgen

AU - Ott, Michael

AU - Buchholz, Christian J.

N1 - Funding Information: T.A. was supported by the DFG-funded Graduate School (GRK1172). This work was supported by grants from the 7th European Community program project “Persist” and by the LOEWE Center for Cell and Gene Therapy Frankfurt, funded by Hessian Ministry of Funding Information: T.A. was supported by the DFG-funded Graduate School (GRK1172). This work was supported by grants from the 7th European Community program project Persist and by the LOEWE Center for Cell and Gene Therapy Frankfurt, funded by Hessian Ministry of Higher Education, Research, and the Arts (III L 4- 518/17.004 [2010]) to C.J.B. M.O. and G.W. were supported by the Deutsche Forschungsgemeinschaft (SFB 738). Publisher Copyright: ©2013 by The American Society of Hematology. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

PY - 2013

Y1 - 2013

N2 - Different types of endothelial cells (EC) fulfill distinct tasks depending on their microenvironment. ECs are therefore difficult to genetically manipulate ex vivo for functional studies or gene therapy. We assessed lentiviral vectors (LVs) targeted to the EC surface marker CD105 for in vivo gene delivery. The mouse CD105-specific vector, mCD105-LV, transduced only CD105-positive cells in primary liver cell cultures. Upon systemic injection, strong reporter gene expression was detected in liver where mCD105-LV specifically transduced liver sinusoidal ECs (LSECs) but not Kupffer cells, which were mainly transduced by nontargeted LVs. Tumor ECs were specifically targeted upon intratumoral vector injection. Delivery of the erythropoietin gene withmCD105-LV resulted in substantially increased erythropoietin and hematocrit levels. The human CD105-specific vector (huCD105-LV) transduced exclusively human LSECs in mice transplanted with human liver ECs. Interestingly, when applied at higher dose and in absence of target cells in the liver, huCD105-LV transduced ECs of a human artery transplanted into the descending mouse aorta. The data demonstrate for the first time targeted gene delivery to specialized ECs upon systemic vector administration. This strategy offers novel options to better understand the physiological functions of ECs and to treat genetic diseases such as those affecting blood factors. (Blood. 2013;122(12):2030-2038).

AB - Different types of endothelial cells (EC) fulfill distinct tasks depending on their microenvironment. ECs are therefore difficult to genetically manipulate ex vivo for functional studies or gene therapy. We assessed lentiviral vectors (LVs) targeted to the EC surface marker CD105 for in vivo gene delivery. The mouse CD105-specific vector, mCD105-LV, transduced only CD105-positive cells in primary liver cell cultures. Upon systemic injection, strong reporter gene expression was detected in liver where mCD105-LV specifically transduced liver sinusoidal ECs (LSECs) but not Kupffer cells, which were mainly transduced by nontargeted LVs. Tumor ECs were specifically targeted upon intratumoral vector injection. Delivery of the erythropoietin gene withmCD105-LV resulted in substantially increased erythropoietin and hematocrit levels. The human CD105-specific vector (huCD105-LV) transduced exclusively human LSECs in mice transplanted with human liver ECs. Interestingly, when applied at higher dose and in absence of target cells in the liver, huCD105-LV transduced ECs of a human artery transplanted into the descending mouse aorta. The data demonstrate for the first time targeted gene delivery to specialized ECs upon systemic vector administration. This strategy offers novel options to better understand the physiological functions of ECs and to treat genetic diseases such as those affecting blood factors. (Blood. 2013;122(12):2030-2038).

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DO - https://doi.org/10.1182/blood-2012-11-468579

M3 - Article

C2 - 23884859

SN - 0006-4971

VL - 122

SP - 2030

EP - 2038

JO - Blood

JF - Blood

IS - 12

ER -

Specific gene delivery to liver sinusoidal & artery endothelial cells

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