Mutagenic Analysis of an Adeno-Associated Virus Variant Capable of Simultaneously Promoting Immune Resistance and Robust Gene Delivery

Yoojin Kim, Eunmi Kim, Seokmin Oh, Ye Eun Yoon, Jae Hyung Jang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

In addition to the ability to boost gene delivery efficiency in many therapeutically relevant cells, the capability of circumventing neutralizing antibody (NAb) inactivation is a key prerequisite that gene carriers must fulfill for their extensive applications as therapeutic agents in many gene therapy trials, especially for cancer treatments. This study revealed that a genetically engineered adeno-associated virus (AAV) variant, AAVr3.45, inherently possesses dual beneficial properties as a gene carrier: (i) efficiently delivering therapeutic genes to many clinically valuable cells (e.g., stem or cancer cells) and (ii) effectively bypassing immunoglobulin (IgG) neutralization. Detailed interpretation of the structural features of AAVr3.45, which was previously engineered from AAV2, demonstrated that the LATQVGQKTA peptide at the heparan sulfate proteoglycan binding domain, especially the presence of cationic lysine on the peptide, served as a key motif for dramatically enhancing its gene delivery capabilities, ultimately broadening its tropisms for many cancer cell lines. Furthermore, the substitution of valine on the AAV2 capsid at the amino acid 719 site to methionine functioned as a coordinator for promoting viral resistance against IgG inactivation. The NAb-resistant characteristics of AAVr3.45 were possibly associated with the LATQVGQKTA sequence itself, indicating that its synergistic cooperation with the point mutation (V719M) is required for maximizing its ability to evade NAb inactivation. The potential of AAVr3.45 as a cancer gene therapy agent was confirmed by provoking apoptosis in breast adenocarcinoma by efficiently delivering a pro-apoptotic gene, BIM (Bcl-2-like protein 11), under high titers of human IgG. Thus, the superior aspects of the NAb-resistant AAVr3.45 as a potential therapeutic agent for systemic injection approaches, especially for cancer gene therapy, were highlighted in this study.

Original languageEnglish
Pages (from-to)25-41
Number of pages17
JournalHuman Gene Therapy
Volume29
Issue number1
DOIs
Publication statusPublished - 2018 Jan

Fingerprint

Dependovirus
Neutralizing Antibodies
Genetic Therapy
Genes
Immunoglobulin G
Neoplasm Genes
Heparan Sulfate Proteoglycans
Peptides
Tropism
Neoplastic Stem Cells
Capsid
Valine
Therapeutics
Point Mutation
Methionine
Lysine
Immunoglobulins
Neoplasms
Adenocarcinoma
Breast

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

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title = "Mutagenic Analysis of an Adeno-Associated Virus Variant Capable of Simultaneously Promoting Immune Resistance and Robust Gene Delivery",
abstract = "In addition to the ability to boost gene delivery efficiency in many therapeutically relevant cells, the capability of circumventing neutralizing antibody (NAb) inactivation is a key prerequisite that gene carriers must fulfill for their extensive applications as therapeutic agents in many gene therapy trials, especially for cancer treatments. This study revealed that a genetically engineered adeno-associated virus (AAV) variant, AAVr3.45, inherently possesses dual beneficial properties as a gene carrier: (i) efficiently delivering therapeutic genes to many clinically valuable cells (e.g., stem or cancer cells) and (ii) effectively bypassing immunoglobulin (IgG) neutralization. Detailed interpretation of the structural features of AAVr3.45, which was previously engineered from AAV2, demonstrated that the LATQVGQKTA peptide at the heparan sulfate proteoglycan binding domain, especially the presence of cationic lysine on the peptide, served as a key motif for dramatically enhancing its gene delivery capabilities, ultimately broadening its tropisms for many cancer cell lines. Furthermore, the substitution of valine on the AAV2 capsid at the amino acid 719 site to methionine functioned as a coordinator for promoting viral resistance against IgG inactivation. The NAb-resistant characteristics of AAVr3.45 were possibly associated with the LATQVGQKTA sequence itself, indicating that its synergistic cooperation with the point mutation (V719M) is required for maximizing its ability to evade NAb inactivation. The potential of AAVr3.45 as a cancer gene therapy agent was confirmed by provoking apoptosis in breast adenocarcinoma by efficiently delivering a pro-apoptotic gene, BIM (Bcl-2-like protein 11), under high titers of human IgG. Thus, the superior aspects of the NAb-resistant AAVr3.45 as a potential therapeutic agent for systemic injection approaches, especially for cancer gene therapy, were highlighted in this study.",
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Mutagenic Analysis of an Adeno-Associated Virus Variant Capable of Simultaneously Promoting Immune Resistance and Robust Gene Delivery. / Kim, Yoojin; Kim, Eunmi; Oh, Seokmin; Yoon, Ye Eun; Jang, Jae Hyung.

In: Human Gene Therapy, Vol. 29, No. 1, 01.2018, p. 25-41.

Research output: Contribution to journalArticle

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AB - In addition to the ability to boost gene delivery efficiency in many therapeutically relevant cells, the capability of circumventing neutralizing antibody (NAb) inactivation is a key prerequisite that gene carriers must fulfill for their extensive applications as therapeutic agents in many gene therapy trials, especially for cancer treatments. This study revealed that a genetically engineered adeno-associated virus (AAV) variant, AAVr3.45, inherently possesses dual beneficial properties as a gene carrier: (i) efficiently delivering therapeutic genes to many clinically valuable cells (e.g., stem or cancer cells) and (ii) effectively bypassing immunoglobulin (IgG) neutralization. Detailed interpretation of the structural features of AAVr3.45, which was previously engineered from AAV2, demonstrated that the LATQVGQKTA peptide at the heparan sulfate proteoglycan binding domain, especially the presence of cationic lysine on the peptide, served as a key motif for dramatically enhancing its gene delivery capabilities, ultimately broadening its tropisms for many cancer cell lines. Furthermore, the substitution of valine on the AAV2 capsid at the amino acid 719 site to methionine functioned as a coordinator for promoting viral resistance against IgG inactivation. The NAb-resistant characteristics of AAVr3.45 were possibly associated with the LATQVGQKTA sequence itself, indicating that its synergistic cooperation with the point mutation (V719M) is required for maximizing its ability to evade NAb inactivation. The potential of AAVr3.45 as a cancer gene therapy agent was confirmed by provoking apoptosis in breast adenocarcinoma by efficiently delivering a pro-apoptotic gene, BIM (Bcl-2-like protein 11), under high titers of human IgG. Thus, the superior aspects of the NAb-resistant AAVr3.45 as a potential therapeutic agent for systemic injection approaches, especially for cancer gene therapy, were highlighted in this study.

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