Infectivity-selective oncolytic adenovirus developed by high-throughput screening of adenovirus-formatted library

Yoshiaki Miura, Satoshi Yamasaki, Julia Davydova, Eric Brown, Kazunori Aoki, Selwyn Vickers, Masato Yamamoto

研究成果: Contribution to journalArticle査読

20 被引用数 (Scopus)

抄録

Adenovirus (Ad) is a potent gene-delivery vehicle and has frequently been used for designing oncolytic viruses. However, lack of selectivity on infection has hampered the achievement of sufficient in vivo efficiency. Here, we developed a novel oncolytic virus system, infectivity-selective oncolytic adenovirus (ISOAd), via direct high-throughput screening of a high-diversity targeting-ligand library in adenoviral format. Through our newly designed rescue virus system, the high-diversity Ad library carrying the random seven amino acid sequences ligand-library in the AB-loop of its fiber-knob region (5 × 10 9 diversity) was successfully generated. During the screening of this library with the cells expressing the target molecule (mesothelin, MSLN), the AB-loop sequence of the virus clones converged to one dominant sequence and a novel MSLN-targeting sequence was isolated. The virus with the isolated motif showed selective infectivity to MSLN-positive cells in vitro. In vivo, it exhibited a selective and potent antitumor effect resulted from the viral replication in MSLN-positive xenografts. The ISOAd is a novel class of oncolytic Ad, which has selectivity at the step of transduction. The selectivity at the stage of infection can open new perspectives in oncolytic Ad therapy for various diseases.

本文言語英語
ページ(範囲)139-148
ページ数10
ジャーナルMolecular Therapy
21
1
DOI
出版ステータス出版済み - 1 2013
外部発表はい

All Science Journal Classification (ASJC) codes

  • 分子医療
  • 分子生物学
  • 遺伝学
  • 薬理学
  • 創薬

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