Abstract
Recombinant proteins can be very potent, but their therapeutic application can be strongly hampered by inappropriate distribution, dosage, kinetics or toxic effects. Targeted delivery of proteins such as cytokines would be strongly desirable. DNA therapeutics comprise the delivery of genetic information on a piece of DNA as therapeutic prodrug. This prodrug can be transcribed and translated into a protein (the actual drug) within the target cells, preferably in a tissue-specific and bio-regulated fashion. Basically, two types of nonviral gene transfer systems [1] have been developed: particle-based systems, with DNA packaged into cationic lipids or polymers; and physical techniques which are based on combining DNA with a physical device. Intramuscular administration of naked DNA has already proven as interesting concept for vaccination [2], despite the low efficiency of the method. Two physical device technologies, electroporation and the gene gun, were found to enhance gene expression levels up to 1000- fold over injection of naked DNA alone. This enhancement has also recently been shown by several groups to trigger immune responses against defined antigens in several species [3]. We have generated particle-based systems that can target gene delivery and expression into distant target tissues. We use DNA polyplexes conjugated with cell-binding ligands such as transferrin for receptor-mediated endocytosis. The surface charge of complexes is masked by covalent coating with polyethylenglycol (PEG). Tumor targeting has been demonstrated in mouse models after systemic administration. With systemically applied tumor necrosis factor (TNF) alpha gene, tumor necrosis and regression of tumors was observed, but no systemic TNF-related side effects. Opportunities to apply local or systemic DNA therapeutics for inflammatory diseases will be discussed.
Highlights
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for rheumatoid arthritis (RA)
We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with defined juvenile idiopathic arthritis (JIA)
Our study revealed that AKA was present overall in 18/29 patients (62%) with severe JIA and in 12/26 patients (46,2 %) with non-severe disease, this did not reach statistical significance (P = 0,18)
Summary
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for RA. Anti-CCP concentrations (expressed in Units per mg total IgG) were on average 1.34 times higher in SF compared to serum (n = 20, P < 0.05) or 1.37 when only positive samples were included (n = 11, P < 0.05) Conclusion: Citrullinated antigens are present in the synovia of both RA and control patients with similar prevalence. At higher concentrations (>1ng/μl) of RNA-oligonucleotides unspecific hybridization-signals prevailed in tissues of all diseases (even in normal controls) The combination of both methods (in situ-hybridization and immunohistochemistry) identifies the single cells inside the synovial lining layer which contains the highly expressed RAB3 “Kreisler” (maf B) gene. Conclusions: These data demonstrates for the first time that statins (and fluvastatin) are able to inhibit an endothelial proadhesive and pro-inflammatory phenotype induced by different stimuli including anti-β2GPI antibodies or pro-inflammatory cytokines These findings suggest a potential usefulness for statins in the prevention of the APS pro-atherothrombotic state
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