Gene transfer into rabbit arteries with adeno‐associated virus and adenovirus vectors

Gruchała, Marcin; Bhardwaj, Shalini; Pajusola, Katri; Roy, Himadri; Rissanen, Tuomas T.; Kokina, Ilze; Kholová, Ivana; Markkanen, Johanna E.; Rutanen, Juha; Heikura, Tommi; Alitalo, Kari; Büeler, Hansruedi; Ylä‐Herttuala, Seppo

doi:10.1002/jgm.535

Cited by 64 publications

(81 citation statements)

References 21 publications

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“…18 Furthermore, adenoviral infection selectively infects the vascular endothelium. 19 We injected rabbits with a dose of 2ϫ10 10 plaque-forming units of adenovirus. A similar …”

Section: Discussionmentioning

confidence: 99%

Endothelial 15-Lipoxygenase-1 Overexpression Increases Acetylcholine-Induced Hypotension and Vasorelaxation in Rabbits

et al. 2008

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Abstract-Arachidonic acid is metabolized by the 15-lipoxygenase-1 pathway to the vasodilatory eicosanoids hydroxyepoxyeicosatrienoic acid and trihydroxyeicosatrienoic acid. We determined the in vitro and in vivo effects of the 15-lipoxygenase-1 metabolites in rabbits infected with adenovirus containing cDNA for human 15-lipoxygenase-1 (Ad-15-LO-1). Forty hours after intravenous adenoviral injection, 15-lipoxygenase-1 expression increased in liver and mesenteric arteries 10-fold and 3-fold, respectively. Expression of 15-LO-1 was limited to the endothelium of mesenteric arteries. Overexpression did not occur in tissues from rabbits infected with a ␤-galactosidase containing adenovirus. Trihydroxyeicosatrienoic acid and hydroxy-epoxyeicosatrienoic acid synthesis per milligram of tissue increased by 2.1-and 1.5-fold, respectively, in mesenteric arteries from Ad-15-LO-1-infected rabbits compared with normal rabbits. Pretreatment with a 15-lipoxygenase inhibitor BW755C inhibited the synthesis. NO and prostaglandin-independent, maximal relaxations to acetylcholine were greater in mesenteric arteries from Ad-15-LO-1-infected rabbits (98.3Ϯ1.7%) compared with normal (60.93Ϯ10.5%) and ␤-galactosidase containing adenovirus-infected rabbits (68.3Ϯ7.7%). Pretreatment with BW755C decreased these relaxations. Mean arterial pressure and heart rate did not differ in Ad-15-LO-1-infected rabbits compared with normal or ␤-galactosidase containing adenovirus-infected rabbits.The hypotensive responses to acetylcholine in the presence and absence of inhibition of NO and prostaglandins were greater in Ad-15-LO-1-infected rabbits (Ϫ52Ϯ2% and Ϫ47Ϯ2%) compared with normal (Ϫ31Ϯ3% and Ϫ25Ϯ5%) or ␤-galactosidase containing adenovirus-infected rabbits (Ϫ38Ϯ2% and Ϫ30Ϯ3%). Therefore, increased expression of 15-LO-1 increases acetylcholine relaxation in arteries and hypotensive responses in rabbits because of increased hydroxy-epoxyeicosatrienoic acid and trihydroxyeicosatrienoic acid synthesis. (Hypertension. 2008;51:246-251.)Key Words: endothelium-derived hyperpolarizing factors Ⅲ endothelium Ⅲ adenovirus Ⅲ hypotension Ⅲ mean arterial pressure 1 5-Lipoxygenase-1 (15-LO-1) is expressed in the vascular endothelium. 1 It metabolizes arachidonic acid (AA) to 15-hydroperoxyeicosatetraenoic acid. 15-Hydroperoxyeicosatetraenoic acid is reduced to 15-hydroxyeicosatetraenoic acid or rearranged to 15-hydroxy-11,12-epoxyeicosatrienoic acid and 11-hydroxy-14,15-epoxyeicosatrienoic acid. Hydroxyepoxyeicosatrienoic acids (HEETAs) are further hydrolyzed to 11,12,15-trihydroxyeicosatrienoic acid and 11,14,15-trihydroxyeicosatrienoic acid. 2 Trihydroxyeicosatrienoic acid (THETA) and HEETA relax rabbit arteries. 2,3 In the presence of NO synthase and cyclooxygenase (COX) inhibition, acetylcholine (ACH) and AA relaxed preconstricted rabbit arteries. These relaxations were inhibited by 15-lipoxygenase inhibitors. 3,4 Thus, 15-LO-1 metabolites mediate relaxations to ACH and AA. 15-Hydroxyeicosatetraenoic acid is inactive in rabbit aorta. 5,6 However, 11,12,15-...

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“…18 Furthermore, adenoviral infection selectively infects the vascular endothelium. 19 We injected rabbits with a dose of 2ϫ10 10 plaque-forming units of adenovirus. A similar …”

Section: Discussionmentioning

confidence: 99%

Endothelial 15-Lipoxygenase-1 Overexpression Increases Acetylcholine-Induced Hypotension and Vasorelaxation in Rabbits

et al. 2008

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“…1,2 Although adenoviral vectors revealed only a transient expression and strong inflammatory response after endothelial gene transfer in a rabbit model, adeno-associated virus (AAV) vectors enabled a more sustained transduction of endothelial cells. 3 However, transduction efficiency of endothelial cells was found to be very low in vivo 3,4 and in vitro. 3,5,6 Transduction efficiency of endothelial cells could be increased by introduction of an endothelial-targeting peptide identified by phage display within the AAV capsids or selection of random AAV display peptide libraries on endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

“…3 However, transduction efficiency of endothelial cells was found to be very low in vivo 3,4 and in vitro. 3,5,6 Transduction efficiency of endothelial cells could be increased by introduction of an endothelial-targeting peptide identified by phage display within the AAV capsids or selection of random AAV display peptide libraries on endothelial cells. 7--13 Such retargeted vectors resulted in an increase in transduction rates by about 40-fold.…”

Section: Introductionmentioning

confidence: 99%

Novel random peptide libraries displayed on AAV serotype 9 for selection of endothelial cell-directed gene transfer vectors

et al. 2011

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We have demonstrated the potential of random peptide libraries displayed on adeno-associated virus (AAV)2 to select for AAV2 vectors with improved efficiency for cell type-directed gene transfer. AAV9, however, may have advantages over AAV2 because of a lower prevalence of neutralizing antibodies in humans and more efficient gene transfer in vivo. Here we provide evidence that random peptide libraries can be displayed on AAV9 and can be utilized to select for AAV9 capsids redirected to the cell type of interest. We generated an AAV9 peptide display library, which ensures that the displayed peptides correspond to the packaged genomes and performed four consecutive selection rounds on human coronary artery endothelial cells in vitro. This screening yielded AAV9 library capsids with distinct peptide motifs enabling up to 40-fold improved transduction efficiencies compared with wild-type (wt) AAV9 vectors. Incorporating sequences selected from AAV9 libraries into AAV2 capsids could not increase transduction as efficiently as in the AAV9 context. To analyze the potential on endothelial cells in the intact natural vascular context, human umbilical veins were incubated with the selected AAV in situ and endothelial cells were isolated. Fluorescence-activated cell sorting analysis revealed a 200-fold improved transduction efficiency compared with wt AAV9 vectors. Furthermore, AAV9 vectors with targeting sequences selected from AAV9 libraries revealed an increased transduction efficiency in the presence of human intravenous immunoglobulins, suggesting a reduced immunogenicity. We conclude that our novel AAV9 peptide library is functional and can be used to select for vectors for future preclinical and clinical gene transfer applications.

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“…Importantly, the peak expression of AAVs does not necessarily take weeks but can be achieved in just a few days after the transduction. 48 AAV vectors have shown high transduction efficacy in blood vessel wall, skeletal muscles, heart and liver, which are frequent targets of cardiovascular gene therapy. In the myocardium, they are several orders of magnitude more efficient than naked plasmid DNA.…”

Section: Hurdles Related To Gene Therapy Vectorsmentioning

confidence: 99%

“…This is because gene expression lasting more than 2-3 years has been reported to occur with AAV-2 in human skeletal muscle. 48 …”

Section: Hurdles Related To Gene Therapy Vectorsmentioning

confidence: 99%

Progress and prospects: hurdles to cardiovascular gene therapy clinical trials

2011

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Gene transfer into rabbit arteries with adeno‐associated virus and adenovirus vectors

Cited by 64 publications

References 21 publications

Endothelial 15-Lipoxygenase-1 Overexpression Increases Acetylcholine-Induced Hypotension and Vasorelaxation in Rabbits

Endothelial 15-Lipoxygenase-1 Overexpression Increases Acetylcholine-Induced Hypotension and Vasorelaxation in Rabbits

Novel random peptide libraries displayed on AAV serotype 9 for selection of endothelial cell-directed gene transfer vectors

Progress and prospects: hurdles to cardiovascular gene therapy clinical trials

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