Prolonged and inducible transgene expression in the liver using gutless adenovirus: a potential therapy for liver cancer.
OBJECTIVE
Gene therapy of liver diseases would benefit from systems allowing prolonged, regulable, and tissue-specific transgene expression. We attempted to produce a vector fulfilling these requirements.


METHODS
We 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.


RESULTS
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 10 hours and completely disappeared by 72 hours. 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 24 hours. 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. Treatment of liver metastases with 5 x 10(8) infectious units of GL-Ad/RUmIL-12 plus RU846 resulted in complete tumor regression in all animals.


CONCLUSIONS
Gutless adenoviral vectors allow liver-specific and regulable transgene expression for prolonged periods of time. These vectors are promising tools for gene therapy of liver cancer and could also be useful for other forms of hepatic disease.
Wang
Lin
L
Faculty of Medicine, University of Navarra, Pamplona, Spain.
Hernández-Alcoceba
Rubén
R
Shankar
Vijay
V
Zabala
Maider
M
Kochanek
Stefan
S
Sangro
Bruno
B
Kramer
M Gabriela
MG
Prieto
Jesus
J
Qian
Cheng
C
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D018664:Interleukin-12 / Q000009:adverse effects / Q000235:genetics* / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000009:adverse effects / Q000235:genetics / Q000494:pharmacology; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism; D019076:Transgenes
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D015534:Trans-Activators; D018664:Interleukin-12; D015735:Mifepristone