Circumventing B Cell Responses to Allow for Redosing of Adeno-Associated Virus Vectors

Ertl, Hildegund C.J.

doi:10.1089/hum.2023.162

Cited by 2 publications

References 52 publications

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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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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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Antibodies against the capsid induced after intracranial AAV administration limits second administration in a dose dependent manner

Xu,

Bai,

Lin

et al. 2024

Preprint

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Recombinant adeno-associated virus (rAAV) is a widely used viral vector for gene therapy. However, a limitation of AAV-mediated gene therapy is that patients are typically dosed only once. In this study, we investigated the possiblility to deliver multiple rounds of AAV through intracerebral injections in the mouse brain. We discovered a dose-dependent modulation of the second round AAV infection by the first round AAV injection in the brain-wide scales besides the injection region. High-dose AAV infection increases chemokines CXCL9 and CXCL10 to recruit the parenchymal infiltration of lymphocytes. Surprisingly, the blood-brain-barrier was relatively intact. Brain-wide dissection discovered the likely rountes of the infiltrated lymphocytes through perivascular space and ventricles. Further analysis using B-cell depleted mice revealed that B lymphocytes, but not T lymphocytes, played a critical role in inhibiting the second round AAV infection. Strategies against neutralizing antibodies had limited effects, while reducing the dosage for the first injection or switching the second AAV to a different serotype appeared to be more effective in antagonizing the first round AAV inhibition. Together, these results suggest that mammalian brains are not immunoprivileged for AAV infection, but multiple rounds of AAV gene therapy are still possible if designed carefully with proper doses and serotypes.

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Circumventing B Cell Responses to Allow for Redosing of Adeno-Associated Virus Vectors

Cited by 2 publications

References 52 publications

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

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

Antibodies against the capsid induced after intracranial AAV administration limits second administration in a dose dependent manner

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