Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.4 (RNase H)
 2,751 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antisense gene suppression has been carried out for human ICAM-1, ELAM-1, and VCAM-1 in cultured human umbilical vein endothelial cells (HUVEC) stimulated by lipopolysaccharide, tumor necrosis factor alpha, or interleukin-1 beta. A panel of antisense phosphorothioate oligodeoxyribonucleotides (PS-ODN), complementary to mRNA or pre-mRNA of these molecules, were tested for their gene suppression activity monitored by radioimmunoassay of the respective cell surface adhesion molecules. Sequences targeted by effective antisense PS-ODNs were located throughout the mRNA and pre-mRNA. "Hot spots" of gene suppression sites for each region were observed. Shift of the PS-ODN hybridizing site upstream or downstream by a few bases resulted in drastic change of gene suppression efficiency. In addition to translation arrest and RNase H activity, a third mechanism was proposed for antisense gene suppression, involving multiple binding sites for PS-ODN and the activities of RNase H and RNases other than RNase H. Suppression of ICAM-1, ELAM-1, or VCAM-1 in HUVEC by their antisense PS-ODNs resulted in the reduction of adhesion of monocytes and U937 to HUVEC. This may suggest cooperativity among the adhesion molecule pairs in endothelial-leukocyte adhesion, since decrease of a single adhesion molecule on EC surface significantly reduced cell-cell adherence.
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PMID:Antisense gene suppression against human ICAM-1, ELAM-1, and VCAM-1 in cultured human umbilical vein endothelial cells. 755 71

We have characterized the mechanism of action of an antisense oligodeoxynucleotide (ASO) targeting human endothelial leukocyte adhesion molecule, E-selectin. ISIS 4730, a 20-base ASO designed to be complementary to a region in the 3'-untranslated region (3'-UTR) of human E-selectin, is a potent and specific inhibitor of both mRNA and protein expression in human umbilical vein endothelial cells. Following treatment with ISIS 4730, a lower molecular weight mRNA (3300 bases) species was detected by Northern blot analysis with a corresponding decrease in the mature E-selectin transcript (3875 bases). The ASO-induced low molecular weight mRNA is stable and remains in the nucleus. We demonstrate that ISIS 4730 targets E-selectin pre-mRNA in the nucleus and promotes cleavage of the pre-mRNA at the hybridization site, resulting in prevention of splicing of the last intron. The change in molecular weight of the E-selectin transcript is the result of loss of the 3'-UTR due to ASO-mediated RNA cleavage and retention of the last intron. Cleavage of the E-selectin pre-mRNA appears to be due to endogenous RNase H or a related enzyme activity.
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PMID:Altered mRNA splicing and inhibition of human E-selectin expression by an antisense oligonucleotide in human umbilical vein endothelial cells. 894 3

Alicaforsen (ISIS-2302) is an RNase H-dependent antisense inhibitor of the intercellular adhesion molecule ICAM-1 under development by Isis Pharmaceuticals, for the potential treatment of a variety of inflammatory disorders [175741]. As of April 1997 it was in phase III trials for Crohn's disease (CD); however, the trial failed and, in December 1999, the company suspended development for this indication [352801]. In October 2000, the company re-initiated development in CD [384820] and new phase III trials had begin by May 2001 [409704]. In August 2000, phase II studies of alicaforsen in an enema formulation for ulcerative colitis and a topical formulation for psoriasis were ongoing [378715]. Development of the compound for the potential treatment of rheumatoid arthritis (RA) was discontinued in 1999 [347579]. By the end of 1998, alicaforsen was in phase II trials for kidney transplant rejection. At this time, these trials were expected to finish in mid-1999 [343460]. However, they were ongoing in September 1999, although no further development has been reported for this indication since that time [338672]. In February 1995, Isis Pharmaceuticals and Boehringer Ingelheim (BI) signed a collaborative agreement on cell adhesion inhibitors, including alicaforsen [174111]. By early 1999, Isis and BI were to decide on the next developmental step for alicaforsen following further analyses of its performance against CD [292915], [315439]. Their joint development agreement was terminated in 1999; Isis regained rights to the product and by September 1999 was in talks to license alicaforsen to another partner for CD [338672]. In June 2000, Cytogenix entered into a sponsored research agreement with Baylor College of Medicine at the Texas Medical Center Houston for the use of its ssDNA expression system for the development of antisense strategies directed against intercellular adhesion molecules for the purpose of reducing lung inflammation and injury in disease states and conditions [369677]. US-05514788, and other patents, cover antisense cell adhesion molecule inhibitors [212289], [234792].
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PMID:Alicaforsen. Isis Pharmaceuticals. 1189 Mar 55