Use of in vivo phage display to engineer novel adenoviruses for targeted delivery to the cardiac vasculature

Abstract

a b s t r a c tWe performed in vivo phage display in the stroke prone spontaneously hypertensive rat, a cardiovascular disease model, and the normotensive Wistar Kyoto rat to identify cardiac targeting peptides, and then assessed each in the context of viral gene delivery. We identified both common and strain-selective peptides, potentially indicating ubiquitous markers and those found selectively in dysfunctional microvasculature of the heart. We show the utility of the peptide, DDTRHWG, for targeted gene delivery in human cells and rats in vivo when cloned into the fiber protein of subgroup D adenovirus 19p. This study therefore identifies cardiac targeting peptides by in vivo phage display and the potential of a candidate peptide for vector targeting strategies.

Specific penetration and accumulation of a homing peptide within atherosclerotic plaques of apolipoprotein E-deficient mice

“…LyP-1 penetration into the plaque interior is a unique feature not seen with previously reported plaque homing peptides, which primarily bind to the luminal surface of plaques or to cells close to the luminal surface (5,6,(8)(9)(10)(11)). An example of such peptides is the CREKA peptide in this study, which almost exclusively delivers its payload to the luminal surface of plaques.…”

“…In vivo phage display (4) has been used with some success to identify reagents with improved specificity for plaque targeting (5)(6)(7)(8)(9)(10)(11). We have shown that the pentapeptide CREKA, which binds to fibrin-fibronectin complexes in clotted plasma (12), homes to plaques (10).…”

The myeloid-binding peptide adenoviral vector enables multi-organ vascular endothelial gene targeting

“…These biologics can be genetically manipulated for disease site homing, infection of relevant target cells, and high-level transgene expression 3, 7–9 . Disease site-specific transductional targeting can be accomplished by genetic manipulation of the viral capsid 6, 9 .…”

Combinatorial Peptide Libraries: Mining for Cell-Binding Peptides

“…One recent study isolated the novel peptide DDTRHWG against the cardiac endothelium of hypertensive rats and inserted this peptide into the H1 loop of a modified adenovirus serotype 5 vector (Ad5), termed Ad5/19p, created for its reduced liver tropism. 369 A peptide-directed virus expressing LacZ was able to specifically transduce cardiac endothelium in vivo, with no virus detected in the liver. This proof of principle gene transduction suggests that this same peptide–adenovirus vector may be used to deliver a gene directed at improving cardiac vasculature function.…”