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Preferential targeting of disseminated liver tumours using a recombinant adeno-associated virus vector

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Peruta M Della , A Badar , C Rosales , A Chokshi , Galante E Nathwani , Ran Yan, E Arstad , AM Davidoff , R Williams , MF Lythgoe , AC Nathwani

Original languageEnglish
Article numberFeb;26(2)
Pages (from-to)94-103
JournalHuman Gene Therapy
Early online date8 Jan 2015
E-pub ahead of print8 Jan 2015

King's Authors


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 post-transcriptional 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. Tumour 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 tumour selective vector encoding herpes simplex virus-thymidine kinase (TK) suicide gene resulted in a 7-fold 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.

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