Adenovirus vectors targeting αv integrin or heparan sulfate receptors display different distribution of transgene activity after intramuscular injection

Corrado Cirielli, Francesco Serino, Stefania Straino, Gabriele Toietta, Damiano Abeni, Giorgio Ventoruzzo, Giuseppe Orlando, Paola Mazzanti, Guido Melillo, Thomas J. Whickham, Imre Kovesdi, Paolo Biglioli, Carlo Gaetano, Maurizio C. Capogrossi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Modification of the fiber proteins in replication-deficient adenoviral (Ad) vectors through incorporation of specific receptor-binding motifs may represent a strategy to enhance their tissue targeting capabilities. Methods: In this study, we compared an unmodified Ad (GV10) with two mutated vectors obtained by insertion of specific target sequences that redirect binding, either toward αV integrin (RGD) or heparan sulfate (UTV) cellular receptors, for reporter gene expression spatial distribution in the rabbit skeletal muscle. In a first series of experiments, injection volume was kept constant and activity of a lacZ transgene was evaluated 48 h after injection of the Ad vectors at different doses. In separate experiments, the effects of different volumes of injection at a constant dose of Ad vector were monitored. Results: All vectors evaluated showed a significant increase in the number of lacZ-positive muscle segments, with increasing vector dose. However, in muscles treated with the UTV vector, fewer muscle fibers were β-gal-positive than in GV10 or RGD vector treated animals. In fact, total β-gal activity increased in a dose-dependent fashion in the GV10- and RGD-treated muscles, but not in the UTV-treated ones. Remarkably, in samples from UTV-treated animals, a volume-dependent enhancement of transgene expression was observed during experiments performed at the same dose and different injection volumes. Conclusions: The results of the present study demonstrate that altering Ad affinity for cellular receptors modulates the level and distribution of transgene activity, conferring characteristics that may allow for treatment customization.

Original languageEnglish
Pages (from-to)309-316
Number of pages8
JournalJournal of Gene Medicine
Volume6
Issue number3
DOIs
Publication statusPublished - Mar 2004

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Heparitin Sulfate
Intramuscular Injections
Transgenes
Adenoviridae
Integrins
Muscles
Injections
Reporter Genes
Skeletal Muscle
Rabbits
Gene Expression
Proteins
Therapeutics

Keywords

  • Adenovirus
  • Gene therapy
  • Heparan sulfate receptor
  • Integrins
  • Skeletal muscle

ASJC Scopus subject areas

  • Genetics

Cite this

Adenovirus vectors targeting αv integrin or heparan sulfate receptors display different distribution of transgene activity after intramuscular injection. / Cirielli, Corrado; Serino, Francesco; Straino, Stefania; Toietta, Gabriele; Abeni, Damiano; Ventoruzzo, Giorgio; Orlando, Giuseppe; Mazzanti, Paola; Melillo, Guido; Whickham, Thomas J.; Kovesdi, Imre; Biglioli, Paolo; Gaetano, Carlo; Capogrossi, Maurizio C.

In: Journal of Gene Medicine, Vol. 6, No. 3, 03.2004, p. 309-316.

Research output: Contribution to journalArticle

Cirielli, C, Serino, F, Straino, S, Toietta, G, Abeni, D, Ventoruzzo, G, Orlando, G, Mazzanti, P, Melillo, G, Whickham, TJ, Kovesdi, I, Biglioli, P, Gaetano, C & Capogrossi, MC 2004, 'Adenovirus vectors targeting αv integrin or heparan sulfate receptors display different distribution of transgene activity after intramuscular injection', Journal of Gene Medicine, vol. 6, no. 3, pp. 309-316. https://doi.org/10.1002/jgm.521
Cirielli, Corrado ; Serino, Francesco ; Straino, Stefania ; Toietta, Gabriele ; Abeni, Damiano ; Ventoruzzo, Giorgio ; Orlando, Giuseppe ; Mazzanti, Paola ; Melillo, Guido ; Whickham, Thomas J. ; Kovesdi, Imre ; Biglioli, Paolo ; Gaetano, Carlo ; Capogrossi, Maurizio C. / Adenovirus vectors targeting αv integrin or heparan sulfate receptors display different distribution of transgene activity after intramuscular injection. In: Journal of Gene Medicine. 2004 ; Vol. 6, No. 3. pp. 309-316.
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AU - Cirielli, Corrado

AU - Serino, Francesco

AU - Straino, Stefania

AU - Toietta, Gabriele

AU - Abeni, Damiano

AU - Ventoruzzo, Giorgio

AU - Orlando, Giuseppe

AU - Mazzanti, Paola

AU - Melillo, Guido

AU - Whickham, Thomas J.

AU - Kovesdi, Imre

AU - Biglioli, Paolo

AU - Gaetano, Carlo

AU - Capogrossi, Maurizio C.

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N2 - Background: Modification of the fiber proteins in replication-deficient adenoviral (Ad) vectors through incorporation of specific receptor-binding motifs may represent a strategy to enhance their tissue targeting capabilities. Methods: In this study, we compared an unmodified Ad (GV10) with two mutated vectors obtained by insertion of specific target sequences that redirect binding, either toward αV integrin (RGD) or heparan sulfate (UTV) cellular receptors, for reporter gene expression spatial distribution in the rabbit skeletal muscle. In a first series of experiments, injection volume was kept constant and activity of a lacZ transgene was evaluated 48 h after injection of the Ad vectors at different doses. In separate experiments, the effects of different volumes of injection at a constant dose of Ad vector were monitored. Results: All vectors evaluated showed a significant increase in the number of lacZ-positive muscle segments, with increasing vector dose. However, in muscles treated with the UTV vector, fewer muscle fibers were β-gal-positive than in GV10 or RGD vector treated animals. In fact, total β-gal activity increased in a dose-dependent fashion in the GV10- and RGD-treated muscles, but not in the UTV-treated ones. Remarkably, in samples from UTV-treated animals, a volume-dependent enhancement of transgene expression was observed during experiments performed at the same dose and different injection volumes. Conclusions: The results of the present study demonstrate that altering Ad affinity for cellular receptors modulates the level and distribution of transgene activity, conferring characteristics that may allow for treatment customization.

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