CpG-depleted adeno-associated virus vectors evade immune detection

Faust, Susan M.; Bell, Peter; Cutler, Benjamin J.; Ashley, Scott N.; Zhu, Yanqing; Rabinowitz, Joseph E.; Wilson, James M.

doi:10.1172/jci68205

Cited by 202 publications

(179 citation statements)

References 26 publications

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“…55 AAV vector genomes depleted from the CpG sequences, which bind Toll-like receptor-9, were in fact shown to avoid innate immune recognition and to improve skeletal muscle transduction. 56 The role of adaptive responses in determining the efficiency and duration of AAV transduction in patients seems far more relevant. Although preclinical animal studies had not indicated a significant immune response against these vectors, experience from clinical trials in humans showed clearly that AAV virions cannot completely hide the immune system and that both pre-existing antibodies and cytotoxic T-cell effectors may impair long-term efficacy of gene therapy.…”

Section: Inflammatory and Immune Response To Aav Vectorsmentioning

confidence: 99%

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

Zacchigna

Zentilin

Giacca

2014

Circulation Research

119

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Abstract:The use of vectors based on the small parvovirus adeno-associated virus has gained significant momentum during the past decade. Their high efficiency of transduction of postmitotic tissues in vivo, such as heart, brain, and retina, renders these vectors extremely attractive for several gene therapy applications affecting these organs. Besides functional correction of different monogenic diseases, the possibility to drive efficient and persistent transgene expression in the heart offers the possibility to develop innovative therapies for prevalent conditions, such as ischemic cardiomyopathy and heart failure. Therapeutic genes are not only restricted to protein-coding complementary DNAs but also include short hairpin RNAs and microRNA genes, thus broadening the spectrum of possible applications. In addition, several spontaneous or engineered variants in the virus capsid have recently improved vector efficiency and expanded their tropism. Apart from their therapeutic potential, adeno-associated virus vectors also represent outstanding investigational tools to explore the function of individual genes or gene combinations in vivo, thus providing information that is conceptually similar to that obtained from genetically modified animals. Finally, their single-stranded DNA genome can drive homology-directed gene repair at high efficiency. Here, we review the main molecular characteristics of adeno-associated virus vectors, with a particular view to their applications in the cardiovascular field.

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Section: Inflammatory and Immune Response To Aav Vectorsmentioning

confidence: 99%

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

Zacchigna

Zentilin

Giacca

2014

Circulation Research

119

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“…However, among its drawbacks are host immune responses against the capsid and/or transgene (Boutin et al, 2010;Rogers et al, 2011;Faust et al, 2013;Mingozzi and High, 2013); appropriate transduction of the target tissue (Zincarelli et al, 2008;Pulicherla et al, 2011;Aschauer et al, 2013); size limitation, with an optimal packaging size of *4.7 kb (Dong et al, 1996); and the challenges to produce high-titer vectors in a cost-and time-effective manner (Clément et al, 2009;Doria et al, 2013). Implementation toward large-scale manufacturing of AAV using infectionbased systems (herpes simplex virus type 1 and baculovirus systems) rather than transfection will certainly become inescapable to address the large quantities of virus needed for FDA-required extensive preclinical studies, as well as clinical studies.…”

Section: Introductionmentioning

confidence: 99%

Copackaging of Multiple Adeno-Associated Viral Vectors in a Single Production Step

Doerfler

Byrne

Clément

2014

Human Gene Therapy Methods

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Limiting factors in large preclinical and clinical studies utilizing adeno-associated virus (AAV) for gene therapy are focused on the restrictive packaging capacity, the overall yields, and the versatility of the production methods for single AAV vector production. Furthermore, applications where multiple vectors are needed to provide long expression cassettes, whether because of long cDNA sequences or the need of different regulatory elements, require that each vector be packaged and characterized separately, directly affecting labor and cost associated with such manufacturing strategies. To overcome these limitations, we propose a novel method of vector production that allows for the packaging of multiple expression cassettes in a single transfection step.Here we combined two expression cassettes in predetermined ratios before transfection and empirically demonstrate that the output vector recapitulates the predicted ratios. Titration by quantitative polymerase chain reaction of AAV vector genome copies using shared or unique genetic elements allowed for delineation of the individual vector contribution to the total preparation that showed the predicted differential packaging outcomes. By copackaging green fluorescent protein (GFP) and mCherry constructs, we demonstrate that both vector genome and infectious titers reiterated the ratios utilized to produce the constructs by transfection. Copackaged therapeutic constructs that only differ in transcriptional elements produced a heterogeneous vector population of both constructs in the predefined ratios. This study shows feasibility and reproducibility of a method that allows for two constructs, differing in either transgene or transcription elements, to be efficiently copackaged and characterized simultaneously, reducing cost of manufacturing and release testing.

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“…An AAV2 encoding antigens of HIV-1 was tested in humans with overall disappointing results [113]. The more recently isolated rhesus macaque hybrid AAVrh32/33 in contrast induces in mice very potent and fully functional CD8 + T cells following activation of strong innate immune responses triggered by TLR-9 and may thus provide a better tool for AAV-based vaccine vectors [17, 66,114].…”

Section: Aav Vectorsmentioning

confidence: 99%

Viral vectors as vaccine carriers

Ertl

2016

Current Opinion in Virology

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CpG-depleted adeno-associated virus vectors evade immune detection

Cited by 202 publications

References 26 publications

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

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

Copackaging of Multiple Adeno-Associated Viral Vectors in a Single Production Step

Viral vectors as vaccine carriers

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