Articles: oligonucleotides.
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The effect of IL-10 antisense oligodeoxynucleotides (ODN) on the susceptibility of burned mice to intradermal (i.d.) infection of methicillin-resistant Staphylococcus aureus (MRSA) was studied. Abscesses formed and sepsis did not develop in normal mice infected i.d. with 10(8)CFU/mouse of MRSA. Similarly, sepsis caused by MRSA i.d. infection did not develop and abscesses formed in burned mice treated with IL-10 antisense ODN. ⋯ However, an abscess did not form, and sepsis caused by MRSA i.d. infection developed in burned mice that were inoculated with M2Mϕ. These results indicate that severely burned mice treated with IL-10 antisense ODN are resistant against i.d. infection with MRSA. M1Mϕ appeared in the infection site tissues of severely burned mice that were treated with IL-10 antisense ODN may play a role on the abscess formation and inhibiting sepsis caused by MRSA i.d. infection.
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Critical care medicine · Jul 2012
Antisense inhibition of secretory and cytosolic phospholipase A2 reduces the mortality in rats with sepsis*.
Phospholipase A(2) has been implicated to play a pivotal role in the pathogenesis of sepsis syndrome. The two major forms of phospholipase A(2) isoenzymes, secretory phospholipase A(2) and cytosolic phospholipase A(2), are overexpressed during sepsis. The objective of this study was to test the hypothesis that inhibition of the overexpressed secretory phospholipase A(2) and cytosolic phospholipase A(2) during sepsis benefits the disease's eventual outcome. ⋯ The results demonstrate that antisense strategy against secretory phospholipase A(2) IIa and cytosolic phospholipase A(2) IVa can inhibit their target protein expression in major organs and greatly improve the clinical outcome, i.e., an absolute reduction in 35-day mortality of 30.8%, in rats with sepsis. Our studies, thus, provide an improved method for the treatment of sepsis by targeting multiple forms of phospholipase A(2) isoenzymes with DNA antisense oligomers.
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European heart journal · Jun 2012
ReviewAntisense oligonucleotides for the treatment of dyslipidaemia.
Antisense oligonucleotides (ASOs) are short synthetic analogues of natural nucleic acids designed to specifically bind to a target messenger RNA (mRNA) by Watson-Crick hybridization, inducing selective degradation of the mRNA or prohibiting translation of the selected mRNA into protein. Antisense technology has the ability to inhibit unique targets with high specificity and can be used to inhibit synthesis of a wide range of proteins that could influence lipoprotein levels and other targets. A number of different classes of antisense agents are under development. ⋯ Other targets currently being addressed include apoC-III and apo(a) or Lp(a). By directly inhibiting the synthesis of specific proteins, ASO technology offers a promising new approach to influence the metabolism of lipids and to control lipoprotein levels. Its application to a wide variety of potential targets can be expected if these agents prove to be clinically safe and effective.
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Transthyretin (TTR)-associated amyloidosis is a late-onset autosomal-dominant genetic disease. Over 100 amyloidogenic mutations have been identified in TTR which destabilize the TTR tetramer thereby inducing the formation of amyloid fibrils in tissues such as the heart and peripheral nerves. This disease mainly affects peripheral nerves, causing familial amyloid polyneuropathy (FAP) or heart, causing familial amyloid cardiomyopathy (FAC). ⋯ As expected, treatment with ISIS-TTR(Rx) also produced a significant decrease in plasma RBP4 levels that correlated with reductions in TTR levels. ISIS-TTR(Rx) treatment was well tolerated in both rodents and monkeys and produced a PK/PD profile consistent with prior experiences using this chemistry platform. ISIS-TTR(Rx) is currently under evaluation in a Phase 1 clinical trial in normal healthy volunteers, and interim results of this trial will be presented.