Display of Self-Peptide on Adeno-Associated Virus Capsid Decreases Phagocytic Uptake <i>in Vitro</i>

Robinson, Tawana M.; Chen, Maria Y.; Lam, Michael T.; Ykema, Matthew; Suh, Junghae

doi:10.1021/acssynbio.0c00203

Cited by 5 publications

(6 citation statements)

References 15 publications

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“… 104 Inspired by the self-peptide (SP), a bioactive region of CD47, that acts as a “don’t-eat-me” signal for macrophages, Robinson et al inserted SP onto the capsid of AAV2 to obtain AAV2 mutants with decreased phagocytic susceptibility in vitro. 105 In another study, after injecting the AAV capsid fused to Tregitopes, the human MHC class II epitopes, CD8+ T in splenocytes of mice displayed reduced responses to AAV capsid. 104 , 106 …”

Section: Capsid Modification Strategymentioning

confidence: 98%

Adeno-Associated Virus Engineering and Load Strategy for Tropism Modification, Immune Evasion and Enhanced Transgene Expression

Zhou,

Liu,

Xiao

et al. 2024

IJN

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Gene therapy aims to add, replace or turn off genes to help treat disease. To date, the US Food and Drug Administration (FDA) has approved 14 gene therapy products. With the increasing interest in gene therapy, feasible gene delivery vectors are necessary for inserting new genes into cells. There are different kinds of gene delivery vectors including viral vectors like lentivirus, adenovirus, retrovirus, adeno-associated virus et al, and non-viral vectors like naked DNA, lipid vectors, polymer nanoparticles, exosomes et al, with viruses being the most commonly used. Among them, the most concerned vector is adeno-associated virus (AAV) because of its safety, natural ability to efficiently deliver gene into cells and sustained transgene expression in multiple tissues. In addition, the AAV genome can be engineered to generate recombinant AAV (rAAV) containing transgene sequences of interest and has been proven to be a safe gene vector. Recently, rAAV vectors have been approved for the treatment of various rare diseases. Despite these approvals, some major limitations of rAAV remain, namely nonspecific tissue targeting and host immune response. Additional problems include neutralizing antibodies that block transgene delivery, a finite transgene packaging capacity, high viral titer used for per dose and high cost. To deal with these challenges, several techniques have been developed. Based on differences in engineering methods, this review proposes three strategies: gene engineering-based capsid modification (capsid modification), capsid surface tethering through chemical conjugation (surface tethering), and other formulations loaded with AAV (virus load). In addition, the major advantages and limitations encountered in rAAV engineering strategies are summarized.

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Section: Capsid Modification Strategymentioning

confidence: 98%

Adeno-Associated Virus Engineering and Load Strategy for Tropism Modification, Immune Evasion and Enhanced Transgene Expression

Zhou,

Liu,

Xiao

et al. 2024

IJN

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“…T on the capsid surface. 246 Bucher and colleagues have recently outlined the important role of extra-viral DNA components in AAV suspensions in activating the innate immune response. Their experiment also indicated that treating AAV suspensions with DNase can reduce or even abolish the innate immune response to AAVs without reducing transduction efficiency.…”

Section: Immune Response To Aavmentioning

confidence: 99%

The menace of severe adverse events and deaths associated with viral gene therapy and its potential solution

Kachanov,

Kostyusheva,

Brezgin

et al. 2024

Medicinal Research Reviews

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Over the past decade, in vivo gene replacement therapy has significantly advanced, resulting in market approval of numerous therapeutics predominantly relying on adeno‐associated viral vectors (AAV). While viral vectors have undeniably addressed several critical healthcare challenges, their clinical application has unveiled a range of limitations and safety concerns. This review highlights the emerging challenges in the field of gene therapy. At first, we discuss both the role of biological barriers in viral gene therapy with a focus on AAVs, and review current landscape of in vivo human gene therapy. We delineate advantages and disadvantages of AAVs as gene delivery vehicles, mostly from the safety perspective (hepatotoxicity, cardiotoxicity, neurotoxicity, inflammatory responses etc.), and outline the mechanisms of adverse events in response to AAV. Contribution of every aspect of AAV vectors (genomic structure, capsid proteins) and host responses to injected AAV is considered and substantiated by basic, translational and clinical studies. The updated evaluation of recent AAV clinical trials and current medical experience clearly shows the risks of AAVs that sometimes overshadow the hopes for curing a hereditary disease. At last, a set of established and new molecular and nanotechnology tools and approaches are provided as potential solutions for mitigating or eliminating side effects. The increasing number of severe adverse reactions and, sadly deaths, demands decisive actions to resolve the issue of immune responses and extremely high doses of viral vectors used for gene therapy. In response to these challenges, various strategies are under development, including approaches aimed at augmenting characteristics of viral vectors and others focused on creating secure and efficacious non‐viral vectors. This comprehensive review offers an overarching perspective on the present state of gene therapy utilizing both viral and non‐viral vectors.

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“…Similar to lentivirus, display of the “Self” peptide on the clinically relevant adeno-associated virus vector (AAV) resulted in reduced phagocytic susceptibility of the AAV in vitro . Because AAVs do not have a membrane envelope, the “Self” peptide was directly introduced into an AAV2 capsid protein and flanked by glycine-serine linkers to ensure capsid stability and minimize viral titer loss.…”

Section: “Self” On Viruses Suppresses Phagocytosis and Enhances Gene ...mentioning

confidence: 99%

Suppressing or Enhancing Macrophage Engulfment through the Use of CD47 and Related Peptides

2022

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Foreign particles and microbes are rapidly cleared by macrophages in vivo, although many key aspects of uptake mechanisms remain unclear. “Self” cells express CD47 which functions as an anti-phagocytic ligand for SIRPα on macrophages, particularly when pro-phagocytic ligands such as antibodies are displayed in parallel. Here, we review CD47 and related “Self” peptides as modulators of macrophage uptake. Nanoparticles conjugated with either CD47 or peptides derived from its SIRPα binding site can suppress phagocytic uptake by macrophages in vitro and in vivo, with similar findings for CD47-displaying viruses. Drugs, dyes, and genes as payloads thus show increased delivery to targeted cells. On the other hand, CD47 expression by cancer cells enables such cells to evade macrophages and immune surveillance. This has motivated development of soluble antagonists to CD47-SIRPα, ranging from blocking antibodies in the clinic to synthetic peptides in preclinical models. CD47 and peptides are thus emerging as dual-use phagocytosis modulators against diseases.

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Display of Self-Peptide on Adeno-Associated Virus Capsid Decreases Phagocytic Uptake in Vitro

Cited by 5 publications

References 15 publications

Adeno-Associated Virus Engineering and Load Strategy for Tropism Modification, Immune Evasion and Enhanced Transgene Expression

Adeno-Associated Virus Engineering and Load Strategy for Tropism Modification, Immune Evasion and Enhanced Transgene Expression

The menace of severe adverse events and deaths associated with viral gene therapy and its potential solution

Suppressing or Enhancing Macrophage Engulfment through the Use of CD47 and Related Peptides

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