Articles: oligonucleotides.
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Am. J. Physiol. Renal Physiol. · May 2011
TRPA1 receptor modulation attenuates bladder overactivity induced by spinal cord injury.
The ankyrin-repeat transient receptor potential 1 (TRPA1) has been implicated in pathological conditions of the bladder, but its role in overactive bladder (OAB) following spinal cord injury (SCI) remains unknown. In this study, using a rat SCI model, we assessed the relevance of TRPA1 in OAB induced by SCI. SCI resulted in tissue damage, inflammation, and changes in bladder contractility and in voiding behavior. ⋯ In addition, the cinnamaldehyde-induced bladder contraction was reduced by exposure of the bladder preparations to HC-030031. The efficacy of TRPA1 AS-ODN treatment was confirmed by means of the reduction of TRPA1 expression in the DRG, in the corresponding segment of the spinal cord and in the bladder, specifically in detrusor muscle. The present data show that the TRPA1 activation and upregulation seem to exert an important role in OAB following SCI.
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Local intramuscular administration of the antisense oligonucleotide PRO051 in patients with Duchenne's muscular dystrophy with relevant mutations was previously reported to induce the skipping of exon 51 during pre-messenger RNA splicing of the dystrophin gene and to facilitate new dystrophin expression in muscle-fiber membranes. The present phase 1-2a study aimed to assess the safety, pharmacokinetics, and molecular and clinical effects of systemically administered PRO051. ⋯ Systemically administered PRO051 showed dose-dependent molecular efficacy in patients with Duchenne's muscular dystrophy, with a modest improvement in the 6-minute walk test after 12 weeks of extended treatment. (Funded by Prosensa Therapeutics; Netherlands National Trial Register number, NTR1241.).
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J. Am. Coll. Cardiol. · Apr 2011
Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice.
This study sought to assess whether an antisense oligonucleotide (ASO) directed to apolipoprotein (a) [apo(a)] reduces apo(a) and lipoprotein (a) [Lp(a)] levels in transgenic mouse models. ⋯ This study documents the first specific therapy, to our knowledge, for lowering apo(a)/Lp(a) levels and their associated OxPL. A more potent effect was documented in mice expressing apo(a) with multiple KIV-2 repeats. Targeting liver expression of apo(a) with ASOs directed to KIV-2 repeats may provide an effective approach to lower elevated Lp(a) levels in humans.
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The therapeutic efficacy of Gem®231, a second generation antisense molecule targeted to the RIα subunit of PKA(RIα) (AS-PKA), administered in combination with androgen deprivation (AD) and radiation therapy (RT), was examined in androgen sensitive (LNCaP) and insensitive (PC3) cell lines. Apoptosis was assayed by Caspase 3 + 7 activity and Annexin V binding. AS-PKA significantly increased apoptosis in vitro from RT (both lines), with further increases in LNCaP cells grown in AD medium. ⋯ PKA(RIα) levels in tumors were quantified via immunohistochemical (IHC) staining and image analysis. IHC measurements in LNCaP cells exhibited that AS-PKA reduced PKA(RIα) levels in vivo. We demonstrate for the first time that AS-PKA enhances cell killing androgen sensitive prostate cancer cells to AD ± RT and androgen insensitive cells to RT.
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Expert Opin Investig Drugs · Feb 2011
ReviewMipomersen, an antisense apolipoprotein B synthesis inhibitor.
mipomersen is a second-generation antisense oligonucleotide (ASO) targeted to human apolipoprotein (apo) B-100, a large protein synthesized by the liver that plays a fundamental role in human lipoprotein metabolism. Mipomersen predominantly distributes to the liver and decreases the production of apoB-100, the primary structural protein of the atherogenic lipoproteins including low density lipoprotein (LDL), thereby reducing plasma LDL-cholesterol and apoB-100 concentrations. ⋯ mipomersen shows promise as an adjunctive agent by reducing apoB-containing lipoproteins in patients at high risk of atherosclerotic cardiovascular disease who are not at target or are intolerant of statins. Although the short-term efficacy and safety of mipomersen has been established, concern exists regarding the long-term potential for hepatic steatosis with this ASO.