title: Preferential targeting of disseminated liver tumors using a recombinant adeno-associated viral vector.
abstract: A novel selectively targeting gene delivery approach has been developed for advanced hepatocellular carcinoma (HCC), a leading cause of cancer mortality whose prognosis remains poor. We combine the strong liver tropism of serotype-8 capsid-pseudotyped adeno-associated viral vectors (AAV8) with a liver-specific promoter (HLP) and microRNA-122a (miR-122a)-mediated posttranscriptional regulation. Systemic administration of our AAV8 construct resulted in preferential transduction of the liver and encouragingly of HCC at heterotopic sites, a finding that could be exploited to target disseminated disease. Tumor selectivity was enhanced by inclusion of miR-122a-binding sequences (ssAAV8-HLP-TK-122aT4) in the expression cassette, resulting in abrogation of transgene expression in normal murine liver but not in HCC. Systemic administration of our tumor-selective vector encoding herpes simplex virus-thymidine kinase (TK) suicide gene resulted in a sevenfold reduction in HCC growth in a syngeneic murine model without toxicity. In summary, we have developed a systemically deliverable gene transfer approach that enables high-level expression of therapeutic genes in HCC but not normal tissues, thus improving the prospects of safe and effective treatment for advanced HCC.
authors.affiliation: 1 Institute of Hepatology, Foundation for Liver Research , London WC1E 6HX, United Kingdom .
authors.forename: Marco
authors.initials: M
authors.lastname: Della Peruta
authors.forename: Adam
authors.initials: A
authors.lastname: Badar
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rosales
authors.forename: Shilpa
authors.initials: S
authors.lastname: Chokshi
authors.forename: Azadeh
authors.initials: A
authors.lastname: Kia
authors.forename: Devhrut
authors.initials: D
authors.lastname: Nathwani
authors.forename: Eva
authors.initials: E
authors.lastname: Galante
authors.forename: Ran
authors.initials: R
authors.lastname: Yan
authors.forename: Erik
authors.initials: E
authors.lastname: Arstad
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.forename: Roger
authors.initials: R
authors.lastname: Williams
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.forename: Amit C
authors.initials: AC
authors.lastname: Nathwani
mesh_terms: D000818:Animals; D002213:Capsid / Q000737:chemistry / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics; D018139:Simplexvirus / Q000737:chemistry / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution; D016042:Transplantation, Heterotopic; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D011994:Recombinant Proteins; D014764:Viral Proteins; D013937:Thymidine Kinase