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Validation of a targeted adenoviral vector efficiently and safely transducing a marker gene in liver tumours in murine models

A targeted adenoviral vector, HC-AdRS24, was validated for its efficient and safe transduction of a marker gene in murine liver tumours models, i.e. to establish pharmacokinetic data in vivo in mice. The vector expresses hIL12 under RU486 inducible control. Different from the mIL12, which at high doses is toxic in mice, the hIL12 does not have functional activity in mice and thus it can be used to analyse expression kinetics. This vector was used

Gene therapy of liver diseases would benefit from systems allowing prolonged, regulatable and tissue-specific transgene expression. We thus attempted to produce a vector fulfilling these requirements and generated gutless adenoviral vectors containing a mifepristone (RU486) inducible system for controlled and liver-specific expression of human interleukin 12 (hIL-12) (GL-Ad/RUhIL-12) and mouse IL-12 (mIL-12) (GL-Ad/RUmIL-12). The properties of these vectors were tested both in vitro and in vivo. We found that infection of cells with GL-Ad/RUhIL-12 resulted in high level of hIL-12 expression in the presence of RU486 only in hepatocytic cells. In animals injected with GL-Ad/RUhIL-12 the administration of RU486 induced a transient rise of serum hIL-12 that peaked at 10h and completely disappeared by 72h. The peak value of hIL-12 was dependent on the doses of the vector and the inducer. High and sustained serum levels of hIL-12 could be attained by continuing administration of RU486 every 12 or 24h. Repetitive induction of hIL-12 could be obtained over, at least, a period of 48 weeks after a single injection of GL-Ad/RUhIL-12.
Although the vector was detected in many tissues after systemic injection, transcription of the transgene was only found in the liver. In conclusion, gutless adenoviral vectors allow liver-specific and regulatable transgene expression for prolonged periods of time. Thus, these vectors are promising tools for gene therapy of liver cancer and could also be useful for other forms of hepatic disease. Indeed, treatment of liver metastases with 5x108 iu of GL-Ad/RUmIL-12 plus RU846 resulted in complete tumour regression in all animals.

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University of Navarra, Division of Hepatology and Gene Therapy, CIMA
C/Irunlarrea, 1
31008 Pamplona
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