Targeting of adenovirus vectors to the LRP receptor family with the high-affinity ligand RAP via combined genetic and chemical modification of the pIX capsomere

Molecular Therapy : the Journal of the American Society of Gene Therapy
Stéphanie CorjonFlorian Kreppel

Abstract

Adenovirus (Ad) vector targeting requires presentation of specific ligands on the virion's surface. Geneti-chemical targeting is based on the genetic introduction of cysteine residues bearing reactive thiol groups into solvent-accessible capsomeres of the virion and subsequent chemical coupling of ligands. Here, we exploited this technology to modify the pIX capsomere with high-affinity ligands. Genetic introduction of C-terminal cysteines to pIX allowed for specific coupling of full-length proteins to the virion, while not affecting vector production. Direct comparison of the two high-affinity ligands receptor- associated protein (RAP) and transferrin (Tf) revealed that targeting after coupling of a high-affinity ligand to pIX presumably requires release of the ligand from its receptor after cell entry. In addition, data obtained by live cell imaging of labeled vector particles demonstrated that coupling of very large proteins to pIX can impair intracellular vector particle trafficking. Finally, we demonstrate that the geneti-chemical targeting technology is suitable for in vivo targeting to liver after intravenous injection. Our data provide significant insight into basic requirements for successful targeting of pIX-modified ...Continue Reading

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Citations

Oct 21, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Jan-Michael PrillFlorian Kreppel
Dec 2, 2009·Human Gene Therapy·Jeroen de VrijGuy Zuber
Nov 2, 2012·Molekuliarnaia biologiia·V A SviatchenkoP M Chumakov
Mar 18, 2016·Atherosclerosis·Yajnavalka BanerjeeManfredi Rizzo
Sep 1, 2017·Human Gene Therapy·Claudia Hagedorn, Florian Kreppel
Mar 28, 2017·Scientific Reports·A M KiveläS Ylä-Herttuala
Mar 7, 2021·International Journal of Molecular Sciences·Florian Kreppel, Claudia Hagedorn
May 1, 2021·Cancers·Nayara Gusmão TessarolloBryan E Strauss

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