Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System

Zacchigna, Serena; Zentilin, Lorena; Giacca, Mauro

doi:10.1161/circresaha.114.302331

Cited by 111 publications

(89 citation statements)

References 195 publications

(198 reference statements)

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“…AAV9 gene delivery in vivo was effective, as concluded by quantitative polymerase chain reaction analysis for vector DNA at days 7, 14, 30, and 60 after transduction (n=3 per group per time; Figure 5A) and in agreement with published observations. 38 In particular, the number of vector genomes in the heart was the highest at 7 days after transduction, decreased at day 14 and remained stable afterward, consistent with our previous results. 26,30 Transgene expression paralleled the levels of transduction and remained relatively high for the whole duration of the experiment ( Figure 5B and 5C for mRNA and protein levels, respectively).…”

Section: Aav-mediated Notch Pathway Activation Is Ineffective After Msupporting

confidence: 92%

Epigenetic Modification at Notch Responsive Promoters Blunts Efficacy of Inducing Notch Pathway Reactivation After Myocardial Infarction

Felician

Collesi

Lušić

et al. 2014

Circulation Research

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Rationale:The Notch pathway plays a key role in stimulating mammalian cardiomyocyte proliferation during development and in the early postnatal life; in adult zebrafish, reactivation of this pathway is also essential to drive cardiac regeneration after injury.Objective: We wanted to assess efficacy of Notch pathway stimulation in neonatal and adult hearts as a means to induce cardiac regeneration after myocardial infarction in mice. Methods and Results:

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Section: Aav-mediated Notch Pathway Activation Is Ineffective After Msupporting

confidence: 92%

Epigenetic Modification at Notch Responsive Promoters Blunts Efficacy of Inducing Notch Pathway Reactivation After Myocardial Infarction

Felician

Collesi

Lušić

et al. 2014

Circulation Research

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“…The fact that optogenetic defibrillation in human diseased hearts is feasible using only epicardial illumination and that cardiac gene expression via AAV in humans is safe (30) suggests the tantalizing possibility that clinical applications might be feasible. Importantly, we were able to demonstrate effective pacing and defibrillation of mouse hearts by epicardial illumination even more than 1 year after the gene transfer.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, we were able to demonstrate effective pacing and defibrillation of mouse hearts by epicardial illumination even more than 1 year after the gene transfer. The great advantage of optogenetic defibrillation is that this would be, in contrast to electrical shocks, pain-free, because ChR2 expression would be restricted to cardiomyocytes by cardiomyocyte-specific AAV vector capsids (30) or promoters (31). Notably, AAV-mediated transduction will result in spatial heterogeneity of ChR2 expression, which is not expected to be pro-arrhythmic per se since ChR2 has neither a leak current in the absence of illumination nor does it affect the electrophysiological properties of cardiomyocytes (5).…”

Section: Discussionmentioning

confidence: 99%

Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations

Bruegmann¹,

Boyle²,

Vogt³

et al. 2016

Journal of Clinical Investigation

149

182

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“…The vectors' intrinsic structural simplicity, lack of pathogenicity, low immunogenicity, and ability to mediate long-term, episomal expression in nondividing cells in vitro and, most notably, postmitotic organs in vivo are desirable characteristics for several gene therapy applications (reviewed in ref. 1). Indeed, to date, over 90 clinical trials using these vectors have been carried out (www.abedia.com/wiley/index.…”

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confidence: 99%

“…This article is a PNAS Direct Submission. 1 To whom correspondence may be addressed. Email: giacca@icgeb.org or mano@icgeb.org.…”

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confidence: 99%

Genome-wide RNAi screening identifies host restriction factors critical for in vivo AAV transduction

Mano

Ippodrino

Zentilin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Viral vectors based on the adeno-associated virus (AAV) hold great promise for in vivo gene transfer; several unknowns, however, still limit the vectors' broader and more efficient application. Here, we report the results of a high-throughput, whole-genome siRNA screening aimed at identifying cellular factors regulating AAV transduction. We identified 1,483 genes affecting vector efficiency more than 4-fold and up to 50-fold, either negatively or positively. Most of these factors have not previously been associated to AAV infection. The most effective siRNAs were independent from the virus serotype or analyzed cell type and were equally evident for single-stranded and self-complementary AAV vectors. A common characteristic of the most effective siRNAs was the induction of cellular DNA damage and activation of a cell cycle checkpoint. This information can be exploited for the development of more efficient AAV-based gene delivery procedures. Administration of the most effective siRNAs identified by the screening to the liver significantly improved in vivo AAV transduction efficiency.adeno-associated virus | DNA-damage response | high-throughput screening | self-complementary vectors | RNA interference V iral vectors based on the adeno-associated virus (AAV) have received incremental attention over the past two decades as effective tools for in vivo gene transfer. The vectors' intrinsic structural simplicity, lack of pathogenicity, low immunogenicity, and ability to mediate long-term, episomal expression in nondividing cells in vitro and, most notably, postmitotic organs in vivo are desirable characteristics for several gene therapy applications (reviewed in ref. 1). Indeed, to date, over 90 clinical trials using these vectors have been carried out (www.abedia.com/wiley/index. html); the first commercial gene therapy product (Glybera) is an AAV1 vector for the treatment of familial lipoprotein lipase deficiency (2).Despite these achievements, AAV vectors still display an undeniable number of limitations in terms of restricted cellular permissivity and efficacy of transgene expression. Efficient transduction in vivo is essentially limited to postmitotic cells [in particular, cardiomyocytes, neurons, retinal cells, and skeletal muscle fibers (1)] and requires infection at a relatively high multiplicity of infection; in addition, vector-driven gene expression is achieved only after a relatively long lag period (3). These characteristics are still incompletely understood in molecular terms but certainly reside within the intrinsic biological properties of target cells. This finding is also highlighted by the peculiar biology of wild-type AAV, which, for the completion of its biological cycle, requires cellular coinfection by adenovirus or other viruses that modify the cellular environment of the target cells, rendering them permissive for viral replication (4-6).The efficient internalization of AAV vectors into different cell types is mediated by the binding of virions to ubiquitously expressed cell surface receptors (...

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Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System

Cited by 111 publications

References 195 publications

Epigenetic Modification at Notch Responsive Promoters Blunts Efficacy of Inducing Notch Pathway Reactivation After Myocardial Infarction

Epigenetic Modification at Notch Responsive Promoters Blunts Efficacy of Inducing Notch Pathway Reactivation After Myocardial Infarction

Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations

Genome-wide RNAi screening identifies host restriction factors critical for in vivo AAV transduction

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