title: Specific gene delivery to liver sinusoidal and 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 with mCD105-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.
authors.affiliation: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Abel
authors.forename: Ebtisam
authors.initials: E
authors.lastname: El Filali
authors.forename: Johan
authors.initials: J
authors.lastname: Waern
authors.forename: Irene C
authors.initials: IC
authors.lastname: Schneider
authors.forename: Qinggong
authors.initials: Q
authors.lastname: Yuan
authors.forename: Robert C
authors.initials: RC
authors.lastname: Münch
authors.forename: Meike
authors.initials: M
authors.lastname: Hick
authors.forename: Gregor
authors.initials: G
authors.lastname: Warnecke
authors.forename: Nodir
authors.initials: N
authors.lastname: Madrahimov
authors.forename: Roland E
authors.initials: RE
authors.lastname: Kontermann
authors.forename: Jörg
authors.initials: J
authors.lastname: Schüttrumpf
authors.forename: Ulrike C
authors.initials: UC
authors.lastname: Müller
authors.forename: Jurgen
authors.initials: J
authors.lastname: Seppen
authors.forename: Michael
authors.initials: M
authors.lastname: Ott
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Buchholz
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001158:Arteries; D002460:Cell Line; D000071063:Endoglin; D042783:Endothelial Cells / Q000378:metabolism*; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008099:Liver; D051379:Mice; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D004921:Erythropoietin