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Pristimerin enhances recombinant adeno-associated virus vector-mediated transgene expression in human cell lines in vitro and murine hepatocytes in vivo

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Journal of Integrative Medicine 2014年第1期12卷 20-34页

作者： Li-na Wang Yuan Wang Yuan Lu Zi-fei Yin Yuan-hui Zhang George V.Aslanidi Arun Srivastava Chang-quan Ling Chen Ling Changhai Hospital of Traditional Chinese Medicine Second Military Medical University Division of Cellular and Molecular Therapy Department of PediatricsUniversity of Florida College of Medicine Powell Gene Therapy Center University of Florida College of Medicine Shanghai University of Traditional Chinese Medicine Department of Orthopaedics and Rehabilitation University of Florida College of Medicine Department of Molecular Genetics and Microbiology University of Florida College of Medicine Genetics Institute University of Florida College of Medicine Shands Cancer Center University of Florida College of Medicine

OBJECTIVE： In the present study, we systemically evaluated the ability of two bioactive compounds from traditional Chinese medicine, celastrol and pristimerin, to enhance recombinant adeno-associated virus （rAAV） serotype vector-mediated transgene expression both in human cell lines in vitro, and in murine hepatocytes in vivo. METHODS： Human cell lines were infected with rAAV vectors with either mock treatment or treatment with celastrol or pristimerin. The transgene expression, percentage of nuclear translocated viral genomes and the ubiquitination of intracellular proteins were investigated post-treatment. In addition, nonobese diabetic/severe combined immunodeficient gamma （NSG） mice were tail vain-injected with rAAV vectors and co-administered with either dimethyl sulfoxide, celastrol, pristimerin or a positive control, bortezomib. The transgene expression in liver was detected and compared over time. RESULTS： We observed that treatment with pristimerin, at as low as 1 IJmol/L concentration, significantly enhanced rAAV2 vector-mediated transgene expression in vitro, and intraperitoneal co- administration with pristimerin at 4 mg/（kg.d） for 3 d dramatically facilitated viral transduction in murine hepatocytes in vivo. The transduction efficiency of the tyrosine-mutant rAAV2 vectors as well as that of rAAV8 vectors carrying oversized transgene cassette was also augmented significantly by pristimerin. The underlying molecular mechanisms by which pristimerin mediated the observed increase in the transduction efficiency of rAAV vectors include both inhibition of proteasomal degradation of the intracellular proteins and enhanced nuclear translocation of the vector genomes. CONCLUSION： These studies suggest the potential beneficial use of pristimerin and pristimerincontaining herb extract in future liver-targeted gene therapy with rAAV vectors.

关键词： celastrol pristimerin adeno-associated viral vector proteosomal inhibitor gene therapy

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