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Synergistic and independent action of endogenous microRNAs 122a and 199a for post-transcriptional liver detargeting of gene vectors

journal contribution
posted on 07.12.2018, 00:00 by B Dhungel, Charmaine Ramlogan-Steel, Jason Steel
In hepatocellular carcinoma (HCC), which usually develops in a cirrhotic liver, treatments preserving normal liver function and viability are vitally important. Here, we utilise the differential expression of miRNAs 122a and 199a between normal hepatocytes and HCC to generate vectors harbouring their binding sites for hepatocyte detargeting. Using a reporter gene, we observed a synergistic detargeting of cells expressing both miRNAs as well as cells expressing either of the miRNAs; while expression was retained in HCC cells negative for both miRNA122a and miRNA199a. Mimics and inhibitors for individual miRNAs were used to confirm these results. Furthermore, suicide gene therapy with cytosine deaminase (CD)/5-fluorocytosine system resulted in limited killing of cells expressing either of the two miRNAs. Finally, we report feasibility of using adeno associated virus (AAV) based vectors for delivery of this dual regulated gene delivery system. These results present a novel dual targeted system whereby miRNA122a and miRNA199a act either synergistically or independently in regulating transgene expression with vectors harbouring binding sites of both miRNAs and have implications in detargeting vectors from multiple cell types in the liver.

Funding

Other

History

Volume

8

Issue

1

Start Page

1

End Page

10

Number of Pages

10

ISSN

2045-2322

Publisher

Nature Publishing Group, UK

Additional Rights

CC BY

Peer Reviewed

Yes

Open Access

Yes

Acceptance Date

01/10/2018

External Author Affiliations

Greenslopes Private Hospital; University of Queensland; 3 University of Queensland Diamantina Institute

Era Eligible

Yes

Journal

Scientific Reports

Licence

Exports

CQUniversity

Licence

Exports