Characterization of the Serpentine Adeno-Associated Virus (SAAV) Capsid Structure: Receptor Interactions and Antigenicity

Mietzsch, Mario; Hull, Joshua A.; Makal, Victoria; Ybargollin, Alberto Jimenez; Yu, Jennifer C.; McKissock, Kedrick; Bennett, Antonette; Pénzes, Judit J.; Lins-Austin, Bridget; Yu, Qian; Chipman, Paul R.; Bhattacharya, Nilakshee; Sousa, Duncan; Strugatsky, David; Tijssen, Peter; McKenna, Robert; Agbandje‐McKenna, Mavis

doi:10.1128/jvi.00335-22

Cited by 9 publications

(4 citation statements)

References 86 publications

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“…Within this framework, AAV tropism and host range have primarily been attributed to interactions of the capsid surface with cell surface carbohydrates and receptors. 6 Paradoxically, non-mammalian isolates such as avian or serpentine AAV, which can engage human glycans, 32 are unable to transduce mammalian cells. 33 Here, while evaluating AAVs of non-mammalian origin, we discover that capsid proteins can exert control over viral genome transcription in a host-specific manner.…”

Section: Discussionmentioning

confidence: 99%

Capsid-mediated control of adeno-associated viral transcription determines host range

Loeb,

Havlik,

Elmore

et al. 2024

Cell Reports

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Section: Discussionmentioning

confidence: 99%

Capsid-mediated control of adeno-associated viral transcription determines host range

Loeb,

Havlik,

Elmore

et al. 2024

Cell Reports

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“…Studies indicate that 40–80% of people have antibodies against known wtAAV serotypes, highlighting the necessity of discovering more sero-distinctive AAVs. 26 , 56 Screening for AAV serotypes in species other than humans and NHPs has been done to find capsids that can avoid the neutralizing effects of encountering pre-existing antibodies against human AAVs, 57 – 60 but these may have limited transduction in humans. Thus, discovering human-derived AAV variants and screening for candidates with enhanced transduction and specific tissue tropism has been a common approach.…”

Section: Aav Biology and Vector Engineeringmentioning

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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“…For the initial reconstruction using icosahedral averaging cisTEM was utilized as reported previously 53,54 . Briefly, the motion-corrected micrographs were imported into the program, and their contrast transfer functions (CTFs) calculated.…”

Section: D Reconstruction Of the Aav9:fab Complexesmentioning

confidence: 99%

Structural characterization of antibody-responses from Zolgensma treatment provides the blueprint for the engineering of an AAV capsid suitable for redosing

Mietzsch,

Nelson,

Hsi

et al. 2024

Preprint

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Monoclonal antibodies (mAbs) are useful tools to dissect the neutralizing antibody response against the adeno-associated virus (AAV) capsids used as gene therapy delivery vectors. This study structurally characterizes the interactions of 21 human-derived antibodies from patients treated with the AAV9 vector, Zolgensma®, utilizing high-resolution cryo-electron microscopy. The majority of the bound antibodies do not conform to the icosahedral symmetry of the capsid, thus requiring localized reconstructions. These complex structures provide unprecedented details of the mAbs binding interfaces, with some antibodies inducing structural perturbations of the capsid upon binding. Key surface capsid amino acid residues were identified facilitating the design of capsid variants with an antibody escape phenotype, with the potential to expand the patient cohort treatable with AAV9 vectors to include those that were previously excluded due to their pre-existing neutralizing antibodies, and possibly also to those requiring redosing.

show abstract

Characterization of the Serpentine Adeno-Associated Virus (SAAV) Capsid Structure: Receptor Interactions and Antigenicity

Abstract: AAVs are widely studied therapeutic gene delivery vectors. However, preexisting antibodies and their detrimental effect on therapeutic efficacy are a primary challenge encountered during clinical trials.

Cited by 9 publications

References 86 publications

Capsid-mediated control of adeno-associated viral transcription determines host range

Capsid-mediated control of adeno-associated viral transcription determines host range

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

Structural characterization of antibody-responses from Zolgensma treatment provides the blueprint for the engineering of an AAV capsid suitable for redosing

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