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Methods and compositions for inhibition of axonal degeneration by modulation of the dlk/jnk pathway

a technology of axonal degeneration and modulation, applied in biochemical apparatus and processes, instruments, biocide, etc., can solve problems such as neurologic impairment, and achieve the effects of slowing the progression of peripheral neuropathy, inhibiting axonal degeneration, and slowing the progression

Inactive Publication Date: 2010-03-04
WASHINGTON UNIV IN SAINT LOUIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0024]In some aspects, the present teaching include methods of treating or slowing progression of a peripheral neuropathy. In various embodiments, these methods comprise administering to a subject in need of treatment an inhibitor of an MLK activity or expression, an inhibitor of JNK activity or expression, or a combination thereof, in an amount effective to inhibit axonal degeneration. In various embodiments, an inhibitor of an MLK activity or expression can be an inhibitor of DLK activity or expression, such as, without limitation, an siRNA against DLK expression. In various embodiments, an inhibitor of an JNK activity or expression can be an inhibitor of activity or expression of JNK1, JNK2 and/or JNK3, such as, without limitation, SP600215.
[0025]In some aspects, the present teaching include methods of treating or slowing progression of a neurodegenerative disease. These methods comprise administering to a subject in need of treatment, an inhibitor of MLK activity or expression, an inhibitor of JNK activity or expression, or a combination thereof, in an amount effective to inhibit axonal degeneration. In various embodiments, an inhibitor of an MLK activity or expression can be an inhibitor of DLK activity or expression, such as, without limitation, an siRNA against DLK expression. In various embodiments, an inhibitor of an JNK activity or expression can be an inhibitor of activity or expression of JNK1, JNK2 and/or JNK3, such as, without limitation, SP600215.
[0026]In some aspects, the present teaching include

Problems solved by technology

Axon loss is a direct cause of neurological impairment and it also often proceeds and promotes cell body dysfunction and death.

Method used

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  • Methods and compositions for inhibition of axonal degeneration by modulation of the dlk/jnk pathway
  • Methods and compositions for inhibition of axonal degeneration by modulation of the dlk/jnk pathway
  • Methods and compositions for inhibition of axonal degeneration by modulation of the dlk/jnk pathway

Examples

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example 1

[0040]This example illustrates that DLK is a component of the molecular pathway that promotes axon degeneration, using a well-established Drosophila axon degeneration model (Hoopfer, E. D., et al., Neuron, 50: 883-895 (2006); MacDonald, J. M., et al., Neuron. 50: 869-881 (2006)). This example further demonstrates that Wallerian degeneration is delayed in Wnd / DLK mutant flies, and that Wnd is required for normal axon degeneration in Drosophila. FIG. 1A presents non-axotomized ORN axons expressing GFP; FIG. 1B presents degenerated WT axons 24 hrs. post-axotomy. FIG. 1C presents Wnd / DLK mutant axons 24 hrs. post-axotomy.

[0041]In this example, the inventors expressed green fluorescent protein (GFP) in a subpopulation of olfactory receptor neurons (ORNs). ORN cell bodies are located peripherally in the antennae, and their axons extend into the brain and terminate glomeruli of both the ipsilateral and contralateral antennal lobes, which are connected by a commissure (FIG. 1A). To sever th...

example 2

[0042]This Example illustrates that normal axon degeneration in response to injury such as axotomy or a toxic chemical such as a cancer chemotherapeutic requires DLK in mammalian neurons.

[0043]In these experiments, the inventors cultured embryonic mouse dorsal root ganglion cells (DRGs) for 14-16 days to allow their axons to radiate from the central core of cell bodies before severing the axons with a micro-scalpel. FIG. 2 shows phase contrast images of DRG axons from DLK mutants and littermate controls. Axotomized DLK mutant axons have a 65%+ / −3.2% (se) decrease in degeneration index (DI) relative to controls (p<0.0001, n=8 individual axotomized DRG cultures per condition, t-test). Vincristine treatment induces 59%+ / −6.3% (se) less DI in DLK mutants relative to controls (p<0.002, n=7 DRG cultures per condition, t-test). As shown in FIG. 2, after 24 hours, transected wild-type axons are dramatically degenerated. The initially smooth and continuous axonal processes become rough and i...

example 3

[0045]This example illustrates that inhibition of JNK during the first three hours of axotomy decreases axonal degeneration.

[0046]In these experiments, to determine whether the axon degeneration pathway requires either JNK or p38, we used pharmacological inhibitors of each MAP kinase in the DRG axotomy model. Wild-type DRG cultures were treated with the JNK inhibitor SP600215 and the p38 inhibitor SB203580 starting from 24 hours before axotomy and for the remainder of the experiment.

[0047]Phase contrast images of DRG axons 24 hours post-axotomy are shown in FIG. 3. Unless noted, vehicle and inhibitors were added 24 hours pre-axotomy and left on for the duration of the experiment. FIG. 3A: Vehicle (DMSO). FIG. 3B: SB203580 (P38 inhibitor). FIG. 3C: SP600215 (JNK inhibitor). FIG. 3D: SP600215 added 24 hr pre-axotomy, and removed just before axotomy. FIG. 3E: SP600215 added concurrently with axotomy. FIG. 3F: SP600215 added 3 hours post-axotomy. FIG. 3G: SP600215 added concurrent with ...

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Abstract

Methods of reducing Wallerian degeneration are disclosed. These methods comprise inhibiting expression or activity of a mixed lineage kinas such as a dual leucine-zipper-bearing kinase (DLK), inhibiting expression or activity of a molecule acting downstream from DLK, such as a c-Jun N-terminal kinase (JNK), or a combination thereof. Further disclosed are methods of screening candidate compounds for DLK inhibition activity. These methods comprise providing a neuronal culture comprising a plurality of axons; contacting the culture with a candidate compound and with an axon degeneration-triggering agent; and comparing axonal degeneration in the culture to a control culture comprising the axon degeneration-triggering agent but not the candidate compound.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application Ser. No. 61 / 091,976 filed on Aug. 26, 2008, which is incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]The disclosed subject matter was developed in part with Government support under grants NS040745 and AG013730 from the National Institutes of Health. The Government has certain rights in the invention.INCORPORATION BY REFERENCE OF SEQUENCE LISTING[0003]The Sequence Listing, which is a part of the present disclosure, includes a computer readable form and a written sequence listing comprising nucleotide and / or amino acid sequences. The sequence listing information recorded in computer readable form is identical to the written sequence listing. The subject matter of the Sequence Listing is incorporated herein by reference in its entirety.INTRODUCTION[0004]Axon degeneration is a common feature of many neurologi...

Claims

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Application Information

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IPC IPC(8): A61K31/7088A61K31/415C12Q1/48
CPCA61K31/415A61K31/7088A61K31/713G01N2333/91205G01N2500/10C12Q1/48
Inventor DIANTONIO, AARONMILLER, BRADLEY R.MILBRANDT, JEFFREY D.PRESS, CRAIG A.
Owner WASHINGTON UNIV IN SAINT LOUIS
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