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AChE antisense oligonucleotide as an anti-inflammatory agent

a technology of anti-inflammatory agents and oligonucleotides, which is applied in the field of anti-inflammatory agents, can solve the problems of mass tremor and spastic paralysis, production and vesicle packaging, mice display early-onset deficits in social recognition, and exaggerated responsiveness to stressful insults

Inactive Publication Date: 2009-01-01
YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The antisense oligonucleotide effectively suppresses the production of pro-inflammatory cytokines such as IL-1β and IL-6, reduces AChE-R mRNA levels, and improves cholinergic homeostasis, providing a novel approach to managing inflammatory conditions and neuropathies by enhancing ACh levels and reducing inflammatory responses.

Problems solved by technology

However, the magnitude and duration of inflammatory responses have to be tightly regulated, because excessive inflammatory reactions can be detrimental, leading to autoimmune diseases, neurodegeneration, sepsis, trauma and other pathological conditions.
These and other acute stressors may induce massive tremor and spastic paralysis, reflecting failure of the quality control processes which presumably act to sustain cholinergic homeostasis in spinal cord motoneurons.
93, 3547-3552], together limiting the production and vesicle packaging of acetylcholine while expediting its degradation.
Furthermore, these mice display early-onset deficits in social recognition and exaggerated responsiveness to stressful insults.
Stressful insults induce AChE-R production in the periphery as well (e.g., in the small intestines), and failure to induce this production, in response to aversive stimuli, results in hypersensitivity to relatively mild stressors [Shapira M. et al.
Nevertheless, several authors reported a rapid resolution of nerve conduction blocks following plasmapheresis, which could not be explained by remyelination or axonal regeneration [Kuwabara S. et al.
In the periphery (e.g., in the small intestines), failure to induce this production in response to aversive stimuli results in hypersensitivity to relatively mild stressors [Shapira (2000) id ibid.].
Major problems remain access to the RNA processing machinery of the cell, potential differences between specific cell types and the mode of chemical protection employed.
When the cell of interest is within the CNS, the problem of access is compounded by the presence of the blood-brain barrier [Tavitian, B. et al.

Method used

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  • AChE antisense oligonucleotide as an anti-inflammatory agent
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  • AChE antisense oligonucleotide as an anti-inflammatory agent

Examples

Experimental program
Comparison scheme
Effect test

example 1

Treatment-Reduced VAChT and ChAT Labeling in Spinal Cord Motoneurons

[0254]VAChT was predictably concentrated in cholinergic (C) terminals surrounding motoneurons [Weihe (1996) id ibid.], where it loads neural vesicles with ACh. Confocal microscopy projections of spinal cord motoneurons (cell diameter=40 μm) from hEN101-treated monkeys as compared with the naïve state showed small but significant dose-independent decreases (p1B), suggesting a handling stress effect on loading C-terminals with ACh. VACh-T-labeled C-terminals were significantly smaller (3) under p.o. administration of 150 μg / kg / day as compared to control sections (FIGS. 1B and 1C, p<0.01, Student's t test), perhaps reflecting changes in VAChT translocation into vesicles and / or VAChT stability.

[0255]VAChT production is largely co-regulated with that of ChAT [Usdin, T. B. et al. (1995) Trends Neurosci. 18, 218-224], since both are produced from one gene complex (the so called “cholinergic locus”) [Erickson, J. D. et al. ...

example 2

EN101 Prevention of Stress-Induced Increases in Plasma AChE Activity

[0256]Cholinesterase activities were measured in plasma samples taken during the second day of hEN101 administration. ATCh hydrolysis in plasma is largely due to serum BuChE, the primary serum cholinesterase encoded by a non-homologous mRNA which remained generally unchanged. However, plasma also includes a minor, but significant AChE activity [Zakut, H. et al. (1998) Cancer 61, 727-737], measurable following pre-incubation in the presence of 5×105M of the BuChE-specific inhibitor, iso-OMPA. AChE activity increased, as compared with the values before treatment (pre-dose), within the 5 hr following the stressful oral gavage administration of 150 μg / kg EN101 (Table 1), potentially reflecting increased production under handling. This further indicates a short half life for primate AChE-R mRNA in vivo, compatible with previous findings [Chan (1991) id ibid; Brenner et al. (2003) id ibid.]. Increases were effectively sup...

example 3

EN101 Effects on AChE-R and ACHE-S mRNAs in Monkey Spinal Cord Neurons

[0257]Paraffin-embedded sections of lumbar spinal cord from Cynomolgus monkeys treated for 7 days once daily with hEN101 were subjected to high resolution fluorescent in situ hybridization (FISH). Variant-specific FISH probes (FIG. 2A) revealed AChE-S more than AChE-R mRNA labeling in numerous punctuate areas and longitudinal threads, possibly cross-sections and longitudinal sections through neuronal processes (FIG. 2B-2C). This difference, albeit statistically non-significant was compatible with previous observations demonstrating AChE-S, but not AChE-R mRNA in murine neuronal processes under normal conditions [Meshorer (2002) id ibid.]. The higher oral and i.v. dose yielded reduced AChE-R mRNA labeling (FIGS. 2G and 2I as compared with the lower dose, FIG. 2E). AChE-S mRNA-labeled neurons displayed limited EN110-induced suppression (FIG. 2H, 2J as compared to 2D), with reduced process labeling (FIGS. 2F, 2H and ...

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Abstract

Disclosed is a novel use for AChE antisense oligonucleotides as anti-inflammatory agents, wherein said oligonucleotides are preferably as denoted by SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:7. Methods of treatment of inflammatory conditions, as well as fever, and particularly inflammation-associated neuropathies such as Guillain-Barré Syndrome, are described.

Description

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH[0001]This work was supported by the US Army Medical Research and Material Command DAMD 17-99-1-9647 (July 1999-August 2004) and the Defense Advance Research Project Agency DARPA N66001-01-C-8015 (May 2001-May 2004). The US Government has certain rights in this invention.FIELD OF THE INVENTION[0002]The present invention relates to the field of anti-inflammatory agents. More specifically, the present invention provides a novel use for an antisense oligonucleotide targeted to the coding domain of the acetylcholinesterase (AChE) nucleotide sequence, as an anti-inflammatory agent.BACKGROUND OF THE INVENTION[0003]All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein.[0004]Inflammation plays a crucial role in defense against pathogen invaders as well as in healing and recovery processes following various types of injury. However, the magnitude and duration of inf...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7105A61K31/7088A61K48/00A61K31/711A61P29/00
CPCA61K31/7088A61K31/712A61K48/00A61P25/00A61P25/18A61P29/00A61P29/02A61P31/04A61P37/00A61P37/02A61P43/00A61P9/10
Inventor SOREQ, HERMONADORI, AMIRWIRGUIN, ITZHAKIFERGANE, GALYIRMIYA, RAZ
Owner YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD