Minicircle DNA is superior to plasmid DNA in eliciting antigen-specific CD8 + T-cell responses

Wynette M. Dietz, Nicole E B Skinner, Sara E. Hamilton, Michelle D. Jund, Suzanne M. Heitfeld, Adam J. Litterman, Patrick Hwu, Zhi Ying Chen, Andres M. Salazar, John R. Ohlfest, Bruce R. Blazar, Christopher A. Pennell, Mark J. Osborn

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Clinical trials reveal that plasmid DNA (pDNA)-based gene delivery must be improved to realize its potential to treat human disease. Current pDNA platforms suffer from brief transgene expression, primarily due to the spread of transcriptionally repressive chromatin initially deposited on plasmid bacterial backbone sequences. Minicircle (MC) DNA lacks plasmid backbone sequences and correspondingly confers higher levels of sustained transgene expression upon delivery, accounting for its success in preclinical gene therapy models. In this study, we show for the first time that MC DNA also functions as a vaccine platform. We used a luciferase reporter transgene to demonstrate that intradermal delivery of MC DNA, relative to pDNA, resulted in significantly higher and persistent levels of luciferase expression in mouse skin. Next, we immunized mice intradermally with DNA encoding a peptide that, when presented by the appropriate major histocompatibility complex class I molecule, was recognized by endogenous CD8 + T cells. Finally, immunization with peptide-encoding MC DNA, but not the corresponding full-length (FL) pDNA, conferred significant protection in mice challenged with Listeria monocytogenes expressing the model peptide. Together, our results suggest intradermal delivery of MC DNA may prove more efficacious for prophylaxis than traditional pDNA vaccines.

Original languageEnglish (US)
Pages (from-to)1526-1535
Number of pages10
JournalMolecular Therapy
Volume21
Issue number8
DOIs
StatePublished - Aug 2013

Bibliographical note

Funding Information:
We thank Stephen Jameson for the OT-I mice, the SIINFEKL/K b -PE tetramer, and critical reading of this manuscript, and Michael Kyba for the hUbC promoter (both of whom are at University of Minnesota). We also thank the staff of the University of Minnesota Masonic Cancer Center Flow Cytometry Core their for assistance. This work was supported by a kind and generous gift to the University of Minnesota Masonic Cancer Center from Rosella Qualey, the Minnesota Futures Grant Program and grants from the NIH (R01 CA72669 and CA113576). W.M.D. was supported in part by a 3M Science and Technology Fellowship. N.E.S. was supported in part by the National Institutes of Health Medical Scientist Training Program Grant (T32 GM008244) and the Graduate School at the University of Minnesota (through the Wilfred Wetzel Fellowship, Warren J Warwick and Henriette Holm Warwick Fellowship, and the Doctoral Dissertation Fellowship). This work was done in Minneapolis, Minnesota, USA. The authors declared no conflict of interest.

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