Immunity to adeno-associated virus serotype 2 delivered transgenes imparted by genetic predisposition to autoimmunity

Zhang, Y. Clare; Powers, Matthew A.; Wasserfall, Clive; Brusko, Todd M.; Song, Sihong; Flotte, Terence R.; Snyder, RO; Potter, Mark; Scott-Jorgensen, Marda; Campbell-Thompson, Martha; Crawford, Julie M.; Nick, HS; Agarwal, Anupam; Ellis, T. M.; Atkinson, M. A.

doi:10.1038/sj.gt.3302144

Cited by 26 publications

(28 citation statements)

References 41 publications

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“…Intra-vitreous injection caused relatively little antibody production ( Figure 7a) compared with the different route of AAV injection used by Zhang et al 16 Li et al 40 demonstrated that a single intra-vitreous injection of AAV2 causes increased AAV antibody production at 2 months after injection. Our data are consistent with their report in terms of the timing of increase and the amount of antibody production (Figure 7a).…”

Section: Side Effect Of Channelrhodopsin-2 Gene Transfer E Sugano Et Almentioning

confidence: 90%

“…However, the titre was extremely low in this study compared with that in a previous report of intramuscular injection of AAV2 (200-400 mg ml À1 ). 16 The titre against the ChR2 protein was the maximum at 6 months post-injection. However, this level was also low (0-4.77 ± 2.55 mg ml À1 ) compared with the antibody level in serum of the immunized rabbit (1442.34 mg ml À1 ), which received a peptide injection to produce antibody to ChR2 forcibly ( Figure 7b).…”

Section: Humoral Immune Responses To the Viral Vector And Transgenementioning

confidence: 95%

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Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy

et al. 2010

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We had previously reported that transduction of the channelrhodopsin-2 (ChR2) gene into retinal ganglion cells restores visual function in genetically blind, dystrophic Royal College of Surgeons (RCS) rats. In this study, we attempted to reveal the safety and influence of exogenous ChR2 gene expression. Adeno-associated virus (AAV) type 2 encoding ChR2 fused to Venus (rAAV-ChR2V) was administered by intra-vitreous injection to dystrophic RCS rats. However, rAAV-ChR2 gene expression was detected in non-target organs (intestine, lung and heart) in some cases. ChR2 function, monitored by recording visually evoked potentials, was stable across the observation period (64 weeks). No change in retinal histology and no inflammatory marker of leucocyte adhesion in the retinal vasculature were observed. Although antibodies to rAAV (0.01-12.21 mg ml À1 ) and ChR2 (0-4.77 mg ml À1 ) were detected, their levels were too low for rejection. T-lymphocyte analysis revealed recognition by T cells and a transient inflammation-like immune reaction only until 1 month after the rAAV-ChR2V injection. In conclusion, ChR2, which originates from Chlamydomonas reinhardtii, can be expressed without immunologically harmful reactions in vivo. These findings will help studies of ChR2 gene transfer to restore vision in progressed retinitis pigmentosa.

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Section: Side Effect Of Channelrhodopsin-2 Gene Transfer E Sugano Et Almentioning

confidence: 90%

Section: Humoral Immune Responses To the Viral Vector And Transgenementioning

confidence: 95%

Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy

et al. 2010

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“…The NOD mouse is a commonly used autoimmune disease model that also displays hypersensitivity to foreign antigen (16). To investigate the immunogenicity of rAAV vectors, cohorts of NOD mice (n ϭ 10) were intraperitoneally (IP) or intramuscularly (IM) injected with rAAV1-hAAT or rAAV8-hAAT vectors (2 ϫ 10 11 particles/mouse).…”

Section: Results Raav1 and Raav8 Vectors Mediated Distinct Immune Resmentioning

confidence: 99%

Distinct immune responses to transgene products from rAAV1 and rAAV8 vectors

Song

2009

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

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Recently developed serotypes of recombinant adeno-associated virus (rAAV) vectors have significantly enhanced the use of rAAV vectors for gene therapy. However, host immune responses to the transgene products from different serotypes remain uncharacterized. In the present study, we evaluated the differential immune responses to the transgene products from rAAV1 and rAAV8 vectors. In non-obese diabetic (NOD) mice, which have a hypersensitive immunity, rAAV serotype 1 vector (rAAV1-hAAT) induced high levels of both humoral and cellular responses, while rAAV8-hAAT did not. In vitro studies showed that rAAV1, but not rAAV8 vector transduced dendritic cells (DCs) efficiently. In vivo studies indicated that vector transduction of DCs was essential for the immune responses; while the presence of a transgene product (or foreign gene product produced by host cells) was not immunogenic. Intriguingly, preimmunization with rAAV8-hAAT vector or with serum of hAAT transgenic NOD mouse induced immune tolerance to rAAV1-hAAT injection. These results demonstrate the immunogenic differences of rAAV1 and rAAV8 and imply tremendous potential for these vectors in different applications, where an immune response to transgene is to be either elicited or avoided. DC activation ͉ rAAV vectors

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“…Furthermore, we have used the common laboratory Balb/c mouse strain as a model, although the genetic background has been shown to impact the immune responsivess, as shown with rAAV2. 42 However, although limited to one animal model, the observation reported here may serve as a basis to further evaluate multiple administration protocols in other strains of mice and larger animal models.…”

Section: Discussionmentioning

confidence: 99%

Long-term expression and repeated administration of AAV type 1, 2 and 5 vectors in skeletal muscle of immunocompetent adult mice

2006

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Adeno-associated viral (AAV) vectors promote long-term gene transfer into muscle in many animal species. Increased expression levels may be obtained by using alternative serotypes in combination with repeated administrations. Here we compared AAV vectors based on serotypes 1, 2 and 5 in immunocompetent mice and assessed the feasibility of multiple administrations of either identical (readministration) or different (cross-administration) serotype-based vectors. A 1-year-long dose-response study confirmed the superiority of recombinant (r)AAV1, achieving transduction levels 5 to 10-fold higher than rAAV2 and rAAV5 in mouse skeletal muscle, respectively. Repeated administration demonstrated that increased gene transfer level was achieved with a second injection of rAAV1 following the first administration of rAAV2 or rAAV5. A readministration study with a vector encoding a different gene allowed the evaluation of gene expression from the second vector only. All three rAAVs were inhibited when the animals were previously exposed to the same serotype. In contrast, no significant change in gene expression from the second vector was observed in cross-administration. A humoral immune response was elicited against the viral capsid for all three serotypes following the initial exposure. Neutralizing antibody (NAB) levels correlated with the vector dose injected. No significant cross-reactivity of NAB from a given serotype toward another was observed in vitro. These data provide the first direct comparative evaluation of re-and cross-administration of rAAV1, rAAV2 and rAAV5 in muscle, and further indicate that rAAV1 is capable of transducing muscle tissue when cross-administered.

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Immunity to adeno-associated virus serotype 2 delivered transgenes imparted by genetic predisposition to autoimmunity

Cited by 26 publications

References 41 publications

Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy

Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy

Distinct immune responses to transgene products from rAAV1 and rAAV8 vectors

Long-term expression and repeated administration of AAV type 1, 2 and 5 vectors in skeletal muscle of immunocompetent adult mice

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