Genetic targeting of an adenovirus vector via replacement of the fiber protein with the phage T4 fibritin.
The utility of adenovirus (Ad) vectors for gene therapy is restricted by their inability to selectively transduce disease-affected tissues. This limitation may be overcome by the derivation of vectors capable of interacting with receptors specifically expressed in the target tissue. Previous attempts to alter Ad tropism by genetic modification of the Ad fiber have had limited success due to structural conflicts between the fiber and the targeting ligand. Here we present a strategy to derive an Ad vector with enhanced targeting potential by a radical replacement of the fiber protein in the Ad capsid with a chimeric molecule containing a heterologous trimerization motif and a receptor-binding ligand. Our approach, which capitalized upon the overall structural similarity between the human Ad type 5 (Ad5) fiber and bacteriophage T4 fibritin proteins, has resulted in the generation of a genetically modified Ad5 incorporating chimeric fiber-fibritin proteins targeted to artificial receptor molecules. Gene transfer studies employing this novel viral vector have demonstrated its capacity to efficiently deliver a transgene payload to the target cells in a receptor-specific manner.
Krasnykh
V
V
Division of Human Gene Therapy, Department of Medicine, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Belousova
N
N
Korokhov
N
N
Mikheeva
G
G
Curiel
D T
DT
D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D017122:Bacteriophage T4 / Q000235:genetics; D002213:Capsid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D036022:Capsid Proteins; D002461:Cell Line, Transformed; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015870:Gene Expression; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011991:Receptors, Virus / Q000378:metabolism; D011995:Recombination, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014771:Virion / Q000378:metabolism
C568771:CLMP protein, human; D036022:Capsid Proteins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D008024:Ligands; D011991:Receptors, Virus; D014764:Viral Proteins; C057839:fibritin protein, Enterobacteria phage T4; C018315:hexon capsid protein, Adenovirus