RESUMO
UNLABELLED: Apolipoprotein C1 (ApoC1) is a component of multiple lipoproteins where it performs a variety of roles in lipid metabolism and transport. ApoC1 exists as both full-length and truncated isoforms. Truncation of ApoC1 has been postulated to result from the action of dipeptidyl peptidase-4 (DPP-4), the target of a new class of diabetes drugs that includes sitagliptin phosphate. In this study, we sought to determine if oral administration of sitagliptin altered the proportion of ApoC1 isoforms circulating in humans. Results indicated a dramatic change in ApoC1 truncation, consistent with a high level of DPP-4 inhibition by sitagliptin. FUNDING: University of Minnesota, Minneapolis, MN, USA.
RESUMO
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.
