4.5 Article

Selective In Vivo Targeting of Human Liver Tumors by Optimized AAV3 Vectors in a Murine Xenograft Model

期刊

HUMAN GENE THERAPY
卷 25, 期 12, 页码 1023-1034

出版社

MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2014.099

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资金

  1. Alex's Lemonade Foundation
  2. Bankhead-Coley Cancer Research Program, Florida Department of Health
  3. Public Health Service Grants from the National Institutes of Health [R01 HL-097088, R21 EB-015684]
  4. Children's Miracle Network
  5. National Natural Science Foundation of China [81273881, 81303112]
  6. E-institutes of Shanghai Municipal Education Commission [E-03008]

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Current challenges for recombinant adeno-associated virus (rAAV) vector-based cancer treatment include the low efficiency and the lack of specificity in vivo. rAAV serotype 3 (rAAV3) vectors have previously been shown to be ineffective in normal mouse tissues following systemic administration. In the present study, we report that rAAV3 vectors can efficiently target and transduce various human liver cancer cells in vivo. Elimination of specific surface-exposed serine and threonine residues on rAAV3 capsids results in further augmentation in the transduction efficiency of these vectors, without any change in the viral tropism and cellular receptor interactions. In addition, we have identified a potential chemotherapy drug, shikonin, as a multifunctional compound to inhibit liver tumor growth as well as to significantly enhance the efficacy of rAAV vector-based gene therapy in vivo. Furthermore, we also document that suppression of tumorigenesis in a human liver cancer xenograft model can be achieved through systemic administration of the optimized rAAV3 vectors carrying a therapeutic gene, and shikonin at a dose that does not lead to liver damage. Our research provides a novel means to achieve not only targeted delivery but also the potential for gene therapy of human liver cancer.

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