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2

项与 Roche Kulmbach GmbH 相关的药物

Targeting ISG15 siRNA (Roche)

靶点

ISG15

作用机制

ISG15基因抑制剂

在研机构-

原研机构

Roche Kulmbach GmbH [+1]

在研适应症-

非在研适应症

丙型肝炎

最高研发阶段终止

首次获批国家/地区-

首次获批日期-

ISG15-LNP01

靶点

ISG15

作用机制

ISG15基因抑制剂

在研机构-

原研机构

Roche Kulmbach GmbH

在研适应症-

非在研适应症

丙型肝炎

最高研发阶段无进展

首次获批国家/地区-

首次获批日期-

100 项与 Roche Kulmbach GmbH 相关的临床结果

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0 项与 Roche Kulmbach GmbH 相关的专利（医药）

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5

项与 Roche Kulmbach GmbH 相关的文献（医药）

2014-01-15·Journal of Virology2区 · 医学

Inosine-Mediated Modulation of RNA Sensing by Toll-Like Receptor 7 (TLR7) and TLR8

2区 · 医学

Article

作者: Behlke, Mark A. ; Tate, Michelle D. ; Miller, Alistair R. ; Gantier, Michael P. ; McCoy, Claire E. ; Mintern, Justine D. ; Jacobi, Ashley M. ; Chen, Weisan ; John, Matthias ; Moffat, Jessica M. ; O'Keeffe, Meredith ; Beckham, Simone A. ; Williams, Bryan R. G. ; Sarvestani, Soroush T.

ABSTRACT RNA-specific adenosine deaminase (ADAR)-mediated adenosine-to-inosine (A-to-I) editing is a critical arm of the antiviral response. However, mechanistic insights into how A-to-I RNA editing affects viral infection are lacking. We posited that inosine incorporation into RNA facilitates sensing of nonself RNA by innate immune sensors and accordingly investigated the impact of inosine-modified RNA on Toll-like receptor 7 and 8 (TLR7/8) sensing. Inosine incorporation into synthetic single-stranded RNA (ssRNA) potentiated tumor necrosis factor alpha (TNF-α) or alpha interferon (IFN-α) production in human peripheral blood mononuclear cells (PBMCs) in a sequence-dependent manner, indicative of TLR7/8 recruitment. The effect of inosine incorporation on TLR7/8 sensing was restricted to immunostimulatory ssRNAs and was not seen with inosine-containing short double-stranded RNAs or with a deoxy-inosine-modified ssRNA. Inosine-mediated increase of self-secondary structure of an ssRNA resulted in potentiated IFN-α production in human PBMCs through TLR7 recruitment, as established through the use of a TLR7 antagonist and Tlr7 -deficient cells. There was a correlation between hyperediting of influenza A viral ssRNA and its ability to stimulate TNF-α, independent of 5′-triphosphate residues, and involving Adar-1. Furthermore, A-to-I editing of viral ssRNA directly enhanced mouse Tlr7 sensing, when present in proportions reproducing biologically relevant levels of RNA editing. Thus, we demonstrate for the first time that inosine incorporation into immunostimulatory ssRNA can potentiate TLR7/8 activation. Our results suggest a novel function of A-to-I RNA editing, which is to facilitate TLR7/8 sensing of phagocytosed viral RNA.

2011-12-01·Nucleic Acid Therapeutics3区 · 医学

Purification of Small Interfering RNA Using Nondenaturing Anion-Exchange Chromatography

3区 · 医学

Article

作者: Debelak, Harald ; Hertel, Frank ; Seiffert, Stephan ; Noll, Bernhard ; Roehl, Ingo ; Hadwiger, Philipp ; Vornlocher, Hans-Peter

A manufacturing and purification process for duplex oligonucleotides was established, which shortens and simplifies currently used procedures, yielding a product of higher purity. The reported procedure is based on nondenaturing anion-exchange (AEX) chromatography, which is performed on the annealed duplex rather than the individual single strands. The duplex is formed early in the process by annealing of the crude single strands directly after solid-phase synthesis. Two 30 μmol manufacturing runs using duplex purification were performed on 2 different AEX resins and compared with a manufacturing run of the same scale using conventional single-strand chromatography. The same pooling strategy was employed for all purifications. Content of optimal duplex (duplex exclusively comprising full-length single strands) was 90.5% and 90.2% for the batches obtained by duplex purification and 86.1% for the batch obtained by single-strand purification. Maximum chromatographic recoveries were 67% for the duplex purification and 68% for the single-strand purification. Hence, the manufacture of small interfering RNA (siRNA) using duplex purification was simpler and faster than conventional single-strand purification and provided better purity and similar yield of final siRNA.

2008-08-19·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates

1区 · 综合性期刊

Article

作者: Koteliansky, Victor ; Maier, Martin ; Hadwiger, Philipp ; Charisse, Klaus ; Wang, Gang ; de Fougerolles, Antonin ; Butler, David ; Dorkin, Robert ; Grefhorst, Aldo ; Bramlage, Birgit ; Vornlocher, Hans-Peter ; Akinc, Akin ; Rajeev, Kallanthottathil G. ; Zimmermann, Tracy ; Röhl, Ingo ; Anderson, Daniel G. ; John, Matthias ; Racie, Timothy S. ; Jayaprakash, K. Narayanannair ; Gamba-Vitalo, Christina ; Frank-Kamenetsky, Maria ; Fan, Yupeng ; Manoharan, Muthiah ; Jayaraman, Muthusamy ; Horton, Jay D. ; Langer, Robert ; Wong, Jamie ; Nechev, Lubomir ; Anderson, Norma N. ; Read, Timothy ; Fitzgerald, Kevin ; Tan, Pamela ; Soutschek, Jürgen

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low density lipoprotein receptor (LDLR) protein levels and function. Loss of PCSK9 increases LDLR levels in liver and reduces plasma LDL cholesterol (LDLc), whereas excess PCSK9 activity decreases liver LDLR levels and increases plasma LDLc. Here, we have developed active, cross-species, small interfering RNAs (siRNAs) capable of targeting murine, rat, nonhuman primate (NHP), and human PCSK9. For in vivo studies, PCSK9 and control siRNAs were formulated in a lipidoid nanoparticle (LNP). Liver-specific siRNA silencing of PCSK9 in mice and rats reduced PCSK9 mRNA levels by 50–70%. The reduction in PCSK9 transcript was associated with up to a 60% reduction in plasma cholesterol concentrations. These effects were shown to be mediated by an RNAi mechanism, using 5′-RACE. In transgenic mice expressing human PCSK9, siRNAs silenced the human PCSK9 transcript by >70% and significantly reduced PCSK9 plasma protein levels. In NHP, a single dose of siRNA targeting PCSK9 resulted in a rapid, durable, and reversible lowering of plasma PCSK9, apolipoprotein B, and LDLc, without measurable effects on either HDL cholesterol (HDLc) or triglycerides (TGs). The effects of PCSK9 silencing lasted for 3 weeks after a single bolus i.v. administration. These results validate PCSK9 targeting with RNAi therapeutics as an approach to specifically lower LDLc, paving the way for the development of PCSK9-lowering agents as a future strategy for treatment of hypercholesterolemia.

100 项与 Roche Kulmbach GmbH 相关的药物交易

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100 项与 Roche Kulmbach GmbH 相关的转化医学

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