Major role of local immune responses in antibody formation to factor IX in AAV gene transfer

Wang, L; Cao, Ou; Swalm, B; Dobrzynski, Eric; Mingozzi, Federico; Herzog, Roland W.

doi:10.1038/sj.gt.3302539

Cited by 88 publications

(91 citation statements)

References 35 publications

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“…We also showed that when using non-(muSeAP) or poorly immunogenic (mTNFR-Is/mIgG1) transgenes, the expression is possible for a longer period of time in dystrophic muscles. Further, in agreement with a previous study, 27 we show that the immune response in healthy mice against an immunogenic transgene such as hTNFR-Is/mIgG1 is dose dependent. Although injection of 5 Â 10 8 and 2 Â 10 9 vg may allow for long-term expression, administration of 1 Â 10 10 resulted in only a transient expression.…”

Section: Discussionsupporting

confidence: 93%

Soluble TNF-α receptor secretion from healthy or dystrophic mice after AAV6-mediated muscle gene transfer

et al. 2010

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Muscle is an attractive target because it is easily accessible; it also offers a permissive environment for adeno-associated virus (AAV)-mediated gene transfer and has an abundant blood vascular supply providing an efficient transport system for the secretion of proteins. However, gene therapy of dystrophic muscle may be more difficult than that of healthy tissue because of degenerative-regenerative processes, and also because of the inflammatory context. In this study we followed the expression levels of secreted inhibitors of the proinflammatory tumor necrosis factor (TNF) cytokine after intramuscular (i.m.) injection of AAV6 into dystrophic mdx and healthy C57BL/10 mice. We used two chimeric proteins, namely, the human or murine TNF-soluble receptor I fused with the murine heavy immunoglobulin chain. We conducted an AAV6 dose-response study and determined the kinetics of transgene expression. In addition, we followed the antibody response against the transgenes and studied their expression pattern in the muscle. Our results show that transduction efficiency is reduced in dystrophic muscles as compared with healthy ones. Furthermore, we found that the immune response against the secreted protein is stronger in mdx mice. Together, our results underscore that the pathological state of the muscle has to be taken into consideration when designing gene therapy approaches.

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Section: Discussionsupporting

confidence: 93%

Soluble TNF-α receptor secretion from healthy or dystrophic mice after AAV6-mediated muscle gene transfer

et al. 2010

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“…Tolerance induction was successful in several strains of mice with an F.IX gene deletion, but induced inhibitors in C3H=HeJ F9 À=À mice (Mingozzi et al, 2003). This strain exhibits stronger B and T cell responses to F.IX than other strains, and higher vector doses are required to achieve therapeutic hepatocyte-derived expression (Mingozzi et al, 2003;Zhang et al, 2004;Wang et al, 2005;Xu et al, 2007). Others have shown that besides the underlying F.IX mutation, several additional genetic factors influence the risk of immune responses on gene transfer.…”

Section: Discussionmentioning

confidence: 99%

Improved Induction of Immune Tolerance to Factor IX by Hepatic AAV-8 Gene Transfer

et al. 2009

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Gene therapy for hemophilia B has been shown to result in long-term expression and immune tolerance to factor IX (F.IX) after in vivo transduction of hepatocytes with adeno-associated viral (AAV-2) vectors in experimental animals. An optimized protocol was effective in several strains of mice with a factor 9 gene deletion (F9 À=À ). However, immune responses against F.IX were repeatedly observed in C3H=HeJ F9 À=À mice. We sought to establish a gene transfer protocol that results in sustained expression without a requirement for additional manipulation of the immune system. Compared with AAV-2, AAV-8 was more efficient in transgene expression and induction of tolerance to F.IX in three different strains of wild-type mice. At equal vector doses, AAV-8 induced transgene product-specific regulatory CD4 + CD25 + FoxP3 + T cells at significantly higher frequency. Moreover, sustained correction of hemophilia B in C3H=HeJ F9 À=À mice without antibody formation was documented in all animals treated with !4Â10 11 vector genomes (VG)=kg and in 80% of mice treated with 8Â10 10 VG=kg. Therefore, it is possible to develop a gene transfer protocol that reliably induces tolerance to F.IX largely independent of genetic factors. A comparison with other studies suggests that additional parameters besides plateau levels of F.IX expression contributed to the improved success rate of tolerance induction.

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“…This result differs from observations made in the liver 35 and may be related to the route of administration, which has been shown to strongly impact the immune response to AAV2. 39,40 This absence of a cross-inhibitory effect following intramuscular rAAV delivery is very encouraging, since a potential limitation of gene therapy efficiency might be the consequence of pre-existing immunity in the patient due to an initial virus exposure.…”

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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Major role of local immune responses in antibody formation to factor IX in AAV gene transfer

Cited by 88 publications

References 35 publications

Soluble TNF-α receptor secretion from healthy or dystrophic mice after AAV6-mediated muscle gene transfer

Soluble TNF-α receptor secretion from healthy or dystrophic mice after AAV6-mediated muscle gene transfer

Improved Induction of Immune Tolerance to Factor IX by Hepatic AAV-8 Gene Transfer

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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