マイクロRNAを利用してウイルス遺伝子の発現を抑制可能な新規アデノウイルスベクターの開発と機能評価

• 清水 かほり

  大阪大谷大学薬学部生化学講座

書誌事項

タイトル別名

• Development and Characterization of a Novel Adenovirus Vector Exhibiting MicroRNA-mediated Suppression of the Leaky Expression of Adenovirus Genes
• マイクロ RNA オ リヨウ シテ ウイルス イデンシ ノ ハツゲン オ ヨクセイ カノウ ナ シンキ アデノウイルス ベクター ノ カイハツ ト キノウ ヒョウカ

抄録

  Replication-incompetent adenovirus (Ad) vectors have gained attention as gene delivery vehicles. Theoretically, no Ad genes should be expressed following transduction; however, Ad genes are expressed from the vector genome, leading to induction of cellular immunity against Ad proteins and Ad protein-induced toxicity. To suppress the leaky expression of Ad genes, a microRNA (miRNA)-regulated gene expression system was utilized. We developed novel Ad vectors by incorporating targeted sequences of miR-122a or miR-142-3p, which exhibit liver- or spleen-specific expression, respectively, in the 3′-untranslated region (UTR) of the E2A, E4, or pIX genes. These Ad vectors easily grew to high titers comparable to those of a conventional Ad vector in conventional human embryonic kidney 293 cells. The leaky expression of these Ad genes in mouse organs was significantly suppressed by 2- to 100-fold in an miRNA-dependent manner, compared with a conventional Ad vector, by the insertion of the miRNA-targeted sequences. Notably, the Ad vector carrying the miR-122a-targeted sequences into the 3′-UTR of the E4 gene (Ad-E4-122aT) expressed 1.5- to 34-fold higher and longer-term transgene expression and more than 20-fold lower levels of all the Ad early and late genes examined in the liver compared with a conventional Ad vector. miR-122a-mediated suppression of E4 gene expression in the liver significantly reduced the hepatotoxicity that an Ad vector causes via both adaptive and non-adaptive immune responses. Ad-E4-122aT would be a promising framework for efficient gene delivery due to its ability to mediate higher and longer-term transgene expression and lower hepatotoxicity than a conventional Ad vector.<br>

収録刊行物

• 薬学雑誌

  薬学雑誌 135 (12), 1349-1356, 2015-12-01

  公益社団法人 日本薬学会

キーワード

• adenovirus vector
• leaky expression
• microRNA
• gene therapy
• hepatotoxicity

詳細情報

• CRID: 1390001206128411136
• NII論文ID: 130005111950
• NII書誌ID: AN00284903
• DOI: 10.1248/yakushi.15-00190
• ISSN: 13475231
• ISSN: 00316903
• NDL書誌ID: 026971705
• PubMed: 26632150
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I026971705
• Web Site: https://www.jstage.jst.go.jp/article/yakushi/135/12/135_15-00190/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2016087143
• 本文言語コード: ja
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• 抄録ライセンスフラグ: 使用不可