Targeting host E-selectin expression by antisense oligodeoxynucleotides as potential antiendotoxin therapy in vivo.

This study sought to determine if antisense oligodeoxynucleotides would inhibit E-selectin expression, which mediates leukocyte adhesion on endothelial cells, otherwise induced by in vivo endotoxin challenge. Six antisense phosphorothioate oligodeoxynucleotides calculated to bind porcine E-selectin mRNA were tested in porcine aortic endothelial cells. One, ISIS9481, exerted significant inhibition of E-selectin expression induced by tumor necrosis factor-α + endotoxin [lipopolysaccharide (LPS)].

Inhibition of protein tyrosine phosphatase-1B with antisense oligonucleotides improves insulin sensitivity and increases adiponectin concentrations in monkeys.

Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates.

Antisense oligonucleotide blockade of alpha 4 integrin prevents and reverses clinical symptoms in murine experimental autoimmune encephalomyelitis.

We investigated the use of an antisense oligonucleotide (ASO) specific for mRNA of the alpha chain (CD49d) of mouse VLA-4 to down-regulate VLA-4 expression and alter central nervous system (CNS) inflammation. ISIS 17044 potently and specifically reduced CD49d mRNA and protein in cell lines and in ex-vivo-treated primary mouse T cells. When administered prophylactically or therapeutically, ISIS 17044 reduced the incidence and severity of paralytic symptoms in a model of experimental autoimmune encephalomyelitis (EAE).

Evaluation of C-5 propynyl pyrimidine-containing oligonucleotides in vitro and in vivo.

Inclusion of C-5 propynyl pyrimidines in phosphorothioate antisense oligonucleotides (ASOs) has been shown to significantly increase their potency for inhibiting gene expression in vitro. This increased potency is believed to be the result of enhanced binding affinity to target RNA. Our results show that C-5 propynyl pyrimidine-modified oligonucleotides caused an increase in the melting temperature (T(m)) of both oligodeoxynucleotides (ODNs) and 2'-O-(2-methoxy)ethyl (2'-MOE)-modified oligonucleotides.

Antisense oligonucleotide blockade of tumor necrosis factor-alpha in two murine models of colitis.

Tumor necrosis factor-alpha (TNF-alpha) is a key cytokine involved in the pathogenesis of inflammatory bowel disease. We have developed a second-generation antisense oligonucleotide (ISIS 25302) specific for murine TNF-alpha and have evaluated this oligonucleotide in two models of gut inflammation of distinct etiology. ISIS 25302 decreased TNF-alpha mRNA in a dose- and sequence-dependent manner in vitro in the mouse macrophage cell line P388D1.

PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice.

The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes was investigated using an antisense oligonucleotide in ob/ob and db/db mice. PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion, and HbA(1C). Hyperinsulinemia was also reduced with improved insulin sensitivity.

Protein tyrosine phosphatase 1B reduction regulates adiposity and expression of genes involved in lipogenesis.

Protein tyrosine phosphatase 1B (PTP1B) has been implicated as a negative regulator of insulin action. Overexpression of PTP1B protein has been observed in insulin-resistant states associated with obesity. Mice lacking a functional PTP1B gene exhibit increased insulin sensitivity and are resistant to weight gain.

Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice.

Signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is crucial for metabolic responses to insulin, and defects in PI3K signaling have been demonstrated in type 2 diabetes. PTEN (MMAC1) is a lipid/protein phosphatase that can negatively regulate the PI3K pathway by dephosphorylating phosphatidylinositol (3,4,5)-triphosphate, but it is unclear whether PTEN is physiologically relevant to insulin signaling in vivo. We employed an antisense oligonucleotide (ASO) strategy in an effort to specifically inhibit the expression of PTEN.