Chemical modification of the adeno-associated virus capsid to improve gene delivery

Mével, Mathieu; Bouzelha, Mohammed; Leray, Aurélien; Pacouret, Simon; Guilbaud, Mickaël; Penaud-Budloo, Magalie; Álvarez-Dorta, Dimitri; Dubreil, Laurence; Gouin, Sébastien G.; Combal, Jean Philippe; Hommel, Mirja; González‐Aseguinolaza, Gloria; Blouin, Véronique; Moullier, Philippe; Adjali, Oumeya; Deniaud, David; Ayuso, Eduard

doi:10.1039/c9sc04189c

Cited by 60 publications

(65 citation statements)

References 38 publications

(54 reference statements)

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“…Recent studies suggest that the AAV DNA sequence per se contributes to tissue toxicity. 47 , 48 Given the relatively low therapeutic index of AAV systemic gene therapy, 49 a high dose of AAV gene delivery is required. However, a high dose of AAV is associated with severe adverse effects.…”

Section: Discussionmentioning

confidence: 99%

High-Resolution Histological Landscape of AAV DNA Distribution in Cellular Compartments and Tissues following Local and Systemic Injection

Zhao

Yue

Wasala

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Adeno-associated virus (AAV) is one of the most important gene delivery vehicles for in vivo gene therapy. Intramuscular (i.m.) and intravascular (i.v.) injection are commonly used for AAV gene transfer. Unfortunately, the fate of AAV vectors following administration remains unclear at the histological level. Taking advantage of RNAscope, a recently developed in situ hybridization technique that can reveal high-resolution viral DNA localization information, in this study, we evaluated body-wide distribution of an AAV9 vector in the context of the cell and tissue microenvironments. We observed distinctive kinetics of cell and nuclear entry of the AAV DNA in striated muscle and liver following i.m. and i.v. injection. We also found characteristic distribution patterns of the AAV DNA in various histological structures in internal organs, including gonads and lymph nodes, following i.v. injection. Finally, we showed significantly body-wide spreading of the AAV DNA following i.m. injection. These results add a new dimension to our understanding of AAV transduction biology and provide a basis for assessing the full impact of AAV gene therapy.

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Section: Discussionmentioning

confidence: 99%

High-Resolution Histological Landscape of AAV DNA Distribution in Cellular Compartments and Tissues following Local and Systemic Injection

Zhao

Yue

Wasala

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…Both systems exhibited lower off-target rates compared with AAV and lentiviral delivery, making it more convenient to deliver specific RNA and ribonucleoprotein for transient Cas9 expression and efficient genome editing. The current study manifests that the genetically and physical–chemical modified viral vectors may further promote the development of gene therapy 205 , 212 .…”

Section: Vnps Vectorsmentioning

confidence: 80%

Recent progress in targeted delivery vectors based on biomimetic nanoparticles

Chen

Hong

Ren

et al. 2021

Sig Transduct Target Ther

164

132

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Over the past decades, great interest has been given to biomimetic nanoparticles (BNPs) since the rise of targeted drug delivery systems and biomimetic nanotechnology. Biological vectors including cell membranes, extracellular vesicles (EVs), and viruses are considered promising candidates for targeted delivery owing to their biocompatibility and biodegradability. BNPs, the integration of biological vectors and functional agents, are anticipated to load cargos or camouflage synthetic nanoparticles to achieve targeted delivery. Despite their excellent intrinsic properties, natural vectors are deliberately modified to endow multiple functions such as good permeability, improved loading capability, and high specificity. Through structural modification and transformation of the vectors, they are pervasively utilized as more effective vehicles that can deliver contrast agents, chemotherapy drugs, nucleic acids, and genes to target sites for refractory disease therapy. This review summarizes recent advances in targeted delivery vectors based on cell membranes, EVs, and viruses, highlighting the potential applications of BNPs in the fields of biomedical imaging and therapy industry, as well as discussing the possibility of clinical translation and exploitation trend of these BNPs.

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“…The simplest involves the attachment to the viral capsid of ligands known to bind to specific receptors present on the surface of hepatocytes. 71,72 Chemical coupling of GalNAc ligands onto lysine residues present on the surface of the AAV capsid has been shown to enhance AAV binding to hepatocytes. 72 AAV capsid variants can also be generated through capsid libraries containing random modifications that are subjected to high throughput in vitro or in vivo selection screens.…”

Section: Vectors Based On Adeno-associated Virus (Aav)mentioning

confidence: 99%

“…71,72 Chemical coupling of GalNAc ligands onto lysine residues present on the surface of the AAV capsid has been shown to enhance AAV binding to hepatocytes. 72 AAV capsid variants can also be generated through capsid libraries containing random modifications that are subjected to high throughput in vitro or in vivo selection screens. 73,74 For this method, capsid libraries can be generated by the insertion of random peptides in specific domains of the capsid or by capsid shuffling.…”

Section: Vectors Based On Adeno-associated Virus (Aav)mentioning

confidence: 99%

Novel vectors and approaches for gene therapy in liver diseases

Maestro

Weber²,

Zabaleta

et al. 2021

JHEP Reports

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Chemical modification of the adeno-associated virus capsid to improve gene delivery

Abstract: Bioconjugated AAV vectors, achieved by coupling of ligands on amino groups of the capsid, are of great interest for gene delivery. Chemical modifications can be used to enhance cell tropism and to decrease interactions with neutralizing antibodies.

Cited by 60 publications

References 38 publications

High-Resolution Histological Landscape of AAV DNA Distribution in Cellular Compartments and Tissues following Local and Systemic Injection

High-Resolution Histological Landscape of AAV DNA Distribution in Cellular Compartments and Tissues following Local and Systemic Injection

Recent progress in targeted delivery vectors based on biomimetic nanoparticles

Novel vectors and approaches for gene therapy in liver diseases

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