Neutralizing Antibodies Against Adeno-Associated Viruses (AAV) in Inflammatory Bowel Disease Patients: Implications for Gene Therapy

Marel, Sander van der; Comijn, Elisabeth M.; Verspaget, Hein W.; Deventer, Sander van; Brink, Gijs R. van den; Petry, Harald; Hommes, Daniël W.; Ferreira, Valérie

doi:10.1016/s0016-5085(11)61827-1

Cited by 2 publications

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“…The cells were washed and fresh growth medium was added. The percentage of transduced cells was measured by determining the number of cells expressing GFP at 48 h after inoculation using flow cytometry and was compared to a control well with no antibody added (van der Marel et al, 2011). The results of three independent experiments are shown.…”

Section: Methodsmentioning

confidence: 99%

“…Humoral immunity leading to virus neutralization has been recognized as a major barrier to clinical trials involving AAV in humans, and the role of cellular immunity is also becoming increasingly appreciated (Boutin et al, 2010;Breous et al, 2011;Calcedo et al, 2009;Mingozzi & High, 2011;van der Marel et al, 2011). Anti-AAV2 neutralizing antibodies have been detected in between 30 and 80 % of human subjects in different studies, and these antibodies are capable of neutralizing the virus and preventing transgene expression (Boutin et al, 2010;Lin et al, 2008;Petry et al, 2008;Zaiss & Muruve, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Examining the cross-reactivity and neutralization mechanisms of a panel of mAbs against adeno-associated virus serotypes 1 and 5

Harbison

Weichert

Gurda

et al. 2012

Journal of General Virology

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Neutralizing antibodies play a central role in the prevention and clearance of viral infections, but can be detrimental to the use of viral capsids for gene delivery. Antibodies present a major hurdle for ongoing clinical trials using adeno-associated viruses (AAVs); however, relatively little is known about the antigenic epitopes of most AAV serotypes or the mechanism(s) of antibody-mediated neutralization. We developed panels of AAV mAbs by repeatedly immunizing mice with AAV serotype 1 (AAV1) capsids, or by sequentially immunizing with AAV1 followed by AAV5 capsids, in order to examine the efficiency and mechanisms of antibody-mediated neutralization. The antibodies were not cross-reactive between heterologous AAV serotypes except for a low level of recognition of AAV1 capsids by the AAV5 antibodies, probably due to the initial immunization with AAV1. The neutralization efficiency of different IgGs varied and Fab fragments derived from these antibodies were generally poorly neutralizing. The antibodies appeared to display various alternative mechanisms of neutralization, which included inhibition of receptor-binding and interference with a post-attachment step. INTRODUCTIONAdeno-associated viruses (AAVs) are non-enveloped viruses with a 4.7 kb ssDNA genome packaged into añ 25 nm diameter icosahedral capsid (Kerr et al., 2006). Several of the 12 currently identified AAV serotypes are under investigation as vectors for therapeutic gene delivery due to features that make them potentially attractive vectors, including high capsid stability and lack of pathogenicity (Allocca et al., 2006;Dai & Rabie, 2007;Grimm & Kay, 2003;Michelfelder & Trepel, 2009; Van Vliet et al., 2008;Wu et al., 2006b). The different serotypes of AAV have viral proteins (VPs) that are~60-90 % identical in amino acid sequence (Gao et al., 2003(Gao et al., , 2004, with variations in capsid surface-oriented loops, resulting in alterations of antigenicity, tissue tropism and transduction efficiency Lerch et al., 2010;Lochrie et al., 2006;Nam et al., 2007;Ng et al., 2010). The AAV2 serotype is the best characterized and is also the capsid type with the largest number of ongoing clinical gene therapy trials (e.g. Grieger & Samulski, 2005;Marks et al., 2010;Mueller & Flotte, 2008;Scallan et al., 2003). Other serotypes such as AAV1 and AAV5 have been less well characterized, but show enhanced transduction of certain tissues such as muscle, brain and/or haematopoietic stem cells compared with AAV2 (Burger et al., 2004;Chao et al., 2000;Zabner et al., 2000;Zhong et al., 2006). Both of these serotypes utilize sialic acids as their primary cellular receptors and AAV5 also binds to the platelet-derived growth factor receptor (PDGFR) as a co-receptor (Kaludov et al., 2001;Di Pasquale et al., 2003;Walters et al., 2001;Wu et al., 2006c).Humoral immunity leading to virus neutralization has been recognized as a major barrier to clinical trials involving AAV in humans, and the role of cellular immunity is also becoming increasingly appreciated (Boutin et al....

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Examining the cross-reactivity and neutralization mechanisms of a panel of mAbs against adeno-associated virus serotypes 1 and 5

Harbison

Weichert

Gurda

et al. 2012

Journal of General Virology

View full text Add to dashboard Cite

show abstract

“…Therefore this promoter is a promising candidate to induce intestine specific expression of a transgene. 22 Another functional disease affecting a large part of the population is nonulcer dyspepsia, defined as impairment of the motility of the upper Gl tract. Delayed emptying of liquids and solids is also a component of other GI disorders such as GERD, and comorbidity of nonulcer dyspepsia occurs with GERD and IBS.…”

Section: Overall Market Size and Anticipated Growthmentioning

confidence: 99%

Gastrointestinal Overview

Evangelista

2013

Reference Module in Chemistry, Molecular Sciences and Chemical Engineering

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Neutralizing Antibodies Against Adeno-Associated Viruses (AAV) in Inflammatory Bowel Disease Patients: Implications for Gene Therapy

Cited by 2 publications

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Examining the cross-reactivity and neutralization mechanisms of a panel of mAbs against adeno-associated virus serotypes 1 and 5

Examining the cross-reactivity and neutralization mechanisms of a panel of mAbs against adeno-associated virus serotypes 1 and 5

Gastrointestinal Overview

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