Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy

Emami, Michael R.; Espinoza, Alejandro; Young, Courtney S.; Ma, Feiyang; Farahat, Philip K.; Felgner, Philip L.; Chamberlain, Jeffrey S.; Xu, Xiang; Pellegrini, Matteo; Villalta, S. Armando; Spencer, Melissa J.

doi:10.1016/j.omtm.2023.06.002

Cited by 7 publications

(2 citation statements)

References 61 publications

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“… 44 , 45 Therefore, our protocol may be useful not only to enable vector re-administration but also to prevent complement activation, which has been found to largely be Abdependent in response to AAV. 44 , 46 , 47 , 48 Similarly, Salabarria et al. demonstrated in study participants receiving systemic high-dose AAV9 gene therapy that α-CD20 and rapamycin IS therapy was able to prevent Ab-mediated induction of the classical pathway and amplification via the alternative pathway of complement activation.…”

Section: Discussionmentioning

confidence: 99%

B cell focused transient immune suppression protocol for efficient AAV readministration to the liver

Rana,

Herzog,

Muñoz-Melero

et al. 2024

Molecular Therapy - Methods & Clinical Development

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Section: Discussionmentioning

confidence: 99%

B cell focused transient immune suppression protocol for efficient AAV readministration to the liver

Rana,

Herzog,

Muñoz-Melero

et al. 2024

Molecular Therapy - Methods & Clinical Development

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“…415 Multiple clinical trials noted the decrease of complement C4 in a subset of rAAV recipients. 416 , 417 In addition, a recent study on patients receiving Zolgensma demonstrated that patients who received steroids alone exhibited higher incidences of TMA and higher AAV9-specific IgM and IgG titers, while patients who received steroids together with rituximab and rapamycin presented lower antibody titers and minimal complement activation. 418 The collective evidence seems to suggest that complement activation in rAAV infusion occurs through the classical pathway.…”

Section: Gene Therapy Efficacy and Clinical Applicationsmentioning

confidence: 99%

Adeno-associated virus as a delivery vector for gene therapy of human diseases

Wang,

Gessler,

Zhan

et al. 2024

Sig Transduct Target Ther

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Adeno-associated virus (AAV) has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different tissues. Recombinant AAV (rAAV) has been engineered for enhanced specificity and developed as a tool for treating various diseases. However, as rAAV is being more widely used as a therapy, the increased demand has created challenges for the existing manufacturing methods. Seven rAAV-based gene therapy products have received regulatory approval, but there continue to be concerns about safely using high-dose viral therapies in humans, including immune responses and adverse effects such as genotoxicity, hepatotoxicity, thrombotic microangiopathy, and neurotoxicity. In this review, we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing technologies. We discuss how rAAVs are being employed in ongoing clinical trials for ocular, neurological, metabolic, hematological, neuromuscular, and cardiovascular diseases as well as cancers. We outline immune responses triggered by rAAV, address associated side effects, and discuss strategies to mitigate these reactions. We hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.

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The presence of CpGs in AAV gene therapy vectors induces a plasmacytoid dendritic cell-like population very early after administration

Glenn,

Negash,

Henry

et al. 2024

Cellular Immunology

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Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy

Cited by 7 publications

References 61 publications

B cell focused transient immune suppression protocol for efficient AAV readministration to the liver

B cell focused transient immune suppression protocol for efficient AAV readministration to the liver

Adeno-associated virus as a delivery vector for gene therapy of human diseases

The presence of CpGs in AAV gene therapy vectors induces a plasmacytoid dendritic cell-like population very early after administration

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