Modifications of adenovirus hexon allow for either hepatocyte detargeting or targeting with potential evasion from Kupffer cells.
In vivo gene transfer with adenovirus vectors would significantly benefit from a tight control of the adenovirus-inherent liver tropism. For efficient hepatocyte transduction, adenovirus vectors need to evade from Kupffer cell scavenging while delivery to peripheral tissues or tumors could be improved if both scavenging by Kupffer cells and uptake by hepatocytes were blocked. Here, we provide evidence that a single point mutation in the hexon capsomere designed to enable defined chemical capsid modifications may permit both detargeting from and targeting to hepatocytes with evasion from Kupffer cell scavenging. Vector particles modified with small polyethylene glycol (PEG) moieties specifically on hexon exhibited decreased transduction of hepatocytes by shielding from blood coagulation factor binding. Vector particles modified with transferrin or, surprisingly, 5,000 Da PEG or dextran increased hepatocyte transduction up to 18-fold independent of the presence of Kupffer cells. We further show that our strategy can be used to target high-capacity adenovirus vectors to hepatocytes emphasizing the potential for therapeutic liver-directed gene transfer. Our approach may lead to a detailed understanding of the interactions between adenovirus vectors and Kupffer cells, one of the most important barriers for adenovirus-mediated gene delivery.
Department of Gene Therapy, University of Ulm, Ulm, Germany.
Jan-Michael
JM
Prill
Sigrid
S
Espenlaub
Ulrike
U
Samen
Tatjana
T
Engler
Erika
E
Schmidt
Francesco
F
Vetrini
Amanda
A
Rosewell
Nathan
N
Grove
Donna
D
Palmer
Philip
P
Ng
Stefan
S
Kochanek
Florian
F
Kreppel
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001779:Blood Coagulation Factors / Q000378:metabolism; D002213:Capsid / Q000378:metabolism; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003911:Dextrans / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology / Q000821:virology*; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism / Q000502:physiology / Q000821:virology*; D008099:Liver / Q000378:metabolism / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017354:Point Mutation; D011092:Polyethylene Glycols / Q000737:chemistry; D014161:Transduction, Genetic / Q000379:methods; D014168:Transferrin / Q000378:metabolism; D018523:Tropism / Q000502:physiology
D001779:Blood Coagulation Factors; D036022:Capsid Proteins; D003911:Dextrans; D014168:Transferrin; C018315:hexon capsid protein, Adenovirus; D011092:Polyethylene Glycols