Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease

Doerfler, Phillip A.; Todd, Adrian G.; Clément, Nathalie; Falk, Darin J.; Nayak, Sushrusha; Herzog, Roland W.; Byrne, Barry J.

doi:10.1089/hum.2015.103

Cited by 47 publications

(49 citation statements)

References 94 publications

(152 reference statements)

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“…Similar effects have been demonstrated following AAV vector administration in mice and dogs with hemophilia B using a high activity factor IX 23 . In Pompe disease rAAV8 vectors have been administered 2–3 weeks following the start of ERT to suppress anti-GAA antibody formation in GAA-KO mice 9, 11. In the current study immune tolerance induction was possible as late as week 25.…”

Section: Discussionsupporting

confidence: 60%

“…Preventing HSATs also reduced mortality from hypersensitivity that had occurred during ERT in GAA-knockout (KO) mice, whereas ERT was efficacious only in the setting of immune tolerance to GAA following AAV vector administration 8 . We and others demonstrated that AAV-vector-mediated gene transfer consistently induced immune tolerance to GAA by expressing GAA exclusively in the liver and by activating regulatory T cells in preclinical experiments 7, 8, 9, 10, 11…”

Section: Introductionmentioning

confidence: 97%

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Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction

Han

Ronzitti

Arnson

et al. 2017

Molecular Therapy - Methods & Clinical Development

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Pompe disease results from acid α-glucosidase (GAA) deficiency, and enzyme replacement therapy (ERT) with recombinant human (rh) GAA has clinical benefits, although its limitations include the short half-life of GAA and the formation of antibody responses. The present study compared the efficacy of ERT against gene transfer with an adeno-associated viral (AAV) vector containing a liver-specific promoter. GAA knockout (KO) mice were administered either a weekly injection of rhGAA (20 mg/kg) or a single injection of AAV2/8-LSPhGAA (8 × 1011 vector genomes [vg]/kg). Both treatments significantly reduced glycogen content of the heart and diaphragm. Although ERT triggered anti-GAA antibody formation, there was no detectable antibody response following AAV vector administration. The efficacy of three lower dosages of AAV2/8-LSPhGAA was evaluated in GAA-KO mice, either alone or in combination with ERT. The minimum effective dose (MED) identified was 8 × 1010 vg/kg to reduce glycogen content in the heart and diaphragm of GAA-KO mice. A 3-fold higher dose was required to suppress antibody responses to ERT. Efficacy from liver gene therapy was slightly greater in male mice than in female mice. Vector dose correlated inversely with anti-GAA antibody formation, whereas higher vector doses suppressed previously formed anti-GAA antibodies as late as 25 weeks after the start of ERT and achieved biochemical correction of glycogen accumulation. In conclusion, we identified the MED for effective AAV2/8-LSPhGAA-mediated tolerogenic gene therapy in Pompe disease mice.

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Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 97%

Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction

Han

Ronzitti

Arnson

et al. 2017

Molecular Therapy - Methods & Clinical Development

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“…5–7,10,12,25,48 A number of studies have documented that liver gene transfer induces systemic immune tolerance, even to nonsecreted antigens. 5,6,9,10,16,19,47–49 This feature makes liver gene transfer attractive as a tolerogenic immune modulatory therapy for multiple diseases. Our data show that liver-draining lymph nodes are a major site of Treg induction.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of antigen presentation to transgene product-specific CD4+ T cells and of Treg induction upon hepatic AAV gene transfer

Perrin

Zolotukhin

Sherman

et al. 2016

Molecular Therapy - Methods & Clinical Development

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The tolerogenic hepatic microenvironment impedes clearance of viral infections but is an advantage in viral vector gene transfer, which often results in immune tolerance induction to transgene products. Although the underlying tolerance mechanism has been extensively studied, our understanding of antigen presentation to transgene product-specific CD4+ T cells remains limited. To address this, we administered hepatotropic adeno-associated virus (AAV8) vector expressing cytoplasmic ovalbumin (OVA) into wt mice followed by adoptive transfer of transgenic OVA-specific T cells. We find that that the liver-draining lymph nodes (celiac and portal) are the major sites of MHC II presentation of the virally encoded antigen, as judged by in vivo proliferation of DO11.10 CD4+ T cells (requiring professional antigen-presenting cells, e.g., macrophages) and CD4+CD25+FoxP3+ Treg induction. Antigen presentation in the liver itself contributes to activation of CD4+ T cells egressing from the liver. Hepatic-induced Treg rapidly disseminate through the systemic circulation. By contrast, a secreted OVA transgene product is presented in multiple organs, and OVA-specific Treg emerge in both the thymus and periphery. In summary, liver draining lymph nodes play an integral role in hepatic antigen presentation and peripheral Treg induction, which results in systemic regulation of the response to viral gene products.

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“…Moreover, the remaining population of transgene product-specific CD4 + T cells is further suppressed by the TGF-β dependent induction of FoxP3 + Treg [81, 85]. Induced Treg suppress antibody and CD8 + T cell responses against the transgene product [87–89]. Higher levels in hepatic transgene expression result in more FoxP3 + Treg induction [82, 83].…”

Section: Immune Tolerance Induction To the Transgene Product By LImentioning

confidence: 99%

“…As a result, immune responses to intravenously injected protein or to transgene expression in other tissues such as CNS or skeletal muscle are prevented [83, 89, 102–104]. Protocols to perform gene transfer to other organs simultaneously with or subsequent to hepatic gene transfer have been successful in pre-clinical studies [29, 89, 102–104]. This strategy represents one potential solution to prevent immune responses to acid α-glucosidase (GAA) in systemic gene therapy for glycogen storage disorder II (Pompe disease).…”

Section: Immune Tolerance Induction To the Transgene Product By LImentioning

confidence: 99%

Complexity of immune responses to AAV transgene products – Example of factor IX

Herzog

2019

Cellular Immunology

Self Cite

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After two decades of research, in vivo gene transfer with adeno-associated viral (AAV) vectors has now resulted in successful treatments and even cures for several human diseases. However, the potential for immune responses against the therapeutic gene products remains one of the concerns as this approach is broadened to more patients, diverse diseases, and target organs. Immune responses following gene transfer of coagulation factor IX (FIX) for the treatment of the bleeding disorder hemophilia B has been extensively investigated in multiple animal models. Findings from these studies have not only influenced clinical trial design but have broader implications for other diseases. The impact of vector design and dose, as well as target organ/route of administration on humoral and cellular immune responses are reviewed. Furthermore, the potential for tolerance induction by hepatic gene transfer or combination with immune modulation is discussed.

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Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease

Cited by 47 publications

References 94 publications

Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction

Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction

Dynamics of antigen presentation to transgene product-specific CD4+ T cells and of Treg induction upon hepatic AAV gene transfer

Complexity of immune responses to AAV transgene products – Example of factor IX

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