Therapeutic agent for motor neuron disease

a technology for motor neuron disease and therapeutic agents, applied in the field of motor neuron disease therapy and/or preventive agents, can solve the problems of no therapeutic agents effective for als, no neuronal cell death inhibitors, and atrophy of voluntary muscles, and achieve the effects of preventing neuronal cell death, and preventing als ons

Inactive Publication Date: 2009-03-19
NOEVIR CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]We have now conducted diligent studies to attaint the object and have consequently completed the present invention by finding out that an activity-dependent neurotrophic factor (hereinafter, referred to as “ADNF”) significantly inhibits (antagonizes) neuronal cell death induced by mutant superoxide dismutase-1 (SOD1) genes and has the effect of improving the motor function of ALS model mice and delaying ALS onset.

Problems solved by technology

ALS causes muscular atrophy and muscular weakness in voluntary muscles in the whole body except for extraocular muscle, and eventually respiratory failure.
Thus, there are no therapeutic agents effective for ALS under present circumstances.
This unique but unfavorable property of ADNF have prevented it from being developed as an anti-Alzheimer's disease (AD) drug.

Method used

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  • Therapeutic agent for motor neuron disease
  • Therapeutic agent for motor neuron disease
  • Therapeutic agent for motor neuron disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

Inhibition of SOD1 Mutant Gene-Induced Neuronal Cell Death by ADNF

(1) Test Materials

[0072]Wild-type SOD1 cDNA (SEQ ID NO: 4) and SOD1 mutant (A4T-SOD1, G85R-SOD1, and G93R-SOD1) cDNAs were kindly provided by Dr. Shoji Tsuji (Faculty of Medicine, the University of Tokyo). Kinase-inactive CaMKII and CaMKIV cDNAs were kindly provided by Dr. Howard Schulman, Stanford University, US. ADNF (SALLRSIPA: SEQ ID NO: 1) and ADNF8 (ALLRSIPA: SEQ ID NO: 2) were synthesized (Glazner G W, et al., 1999, J Neurochem 73: 2341-2347). IPAL peptide (IPALDSLKPANEDQKIGIEI: SEQ ID NO: 3, Zamostiano R, et al., 1999, Neurosci Lett 264: 9-12) was purchased from the Peptide Institute (Osaka, Japan). An anti-SOD1 antibody was purchased from MBL (Nagoya, Japan). PD98059, SB20380, AG490, KN93, KN92, and HA1004 were purchased from Calbiochem-Novabiochem (San Diego, USA).

[0073]F11 cell, the hybrid cell of rat embryonic day 13 (E13) primary cultured neuronal cell with mouse neuroblastoma NTG18 cell, was cultured in ...

example 2

Dose-Dependent Inhibitory Effect of ADNF on Neuronal Cell Death

[0082]F11 or NSC34 cells were used to confirm the dose-dependent effect of ADNF on neuronal cell death induced by transformation with SOD1 mutant genes (A4T-SOD1, G85R-SOD1, and G93R-SOD1).

[0083]F11 or NSC34 cells were transformed with pEF-BOS, A4T-SOD1, G85R-SOD1, or G93R-SOD1 cDNA in the presence of increasing concentrations (10 aM, 1 fM, 100 fM, 10 pM, 1 nM, and 100 nM) of ADNF. After 72 hours, cell mortality was measured by Trypan blue exclusion assay.

[0084]Although 10 aM ADNF hardly exhibited cell death inhibition, 100 fM ADNF completely decreased cell mortalities induced by these three types of SOD1 mutant genes to the level of the control (FIG. 2A). In this regard, the complete protective action of ADNF on cell death caused by the SOD1 mutant genes was observed at the concentrations equal to or above 10 nM. These results demonstrated the dose-dependent inhibitory activity of ADNF against neuronal cell death caused...

example 3

Analysis on Neuroprotective Action of ADNF

[0089]Intracellular signaling by ADNF was examined. F11 cells were transformed with pEF-BOS or SOD1 mutant (A4T-SOD1, G85R-SOD1, or G93R-SOD1) cDNA and reacted with 10 nM wortmannin (PI3 kinase inhibitor), 100 μM genistein (tyrosine kinase inhibitor), 50 μM PD98059 (MEK inhibitor), 20 μM SB203580 (p38 MAPK inhibitor), 1 μM AG490 (JAK kinase inhibitor), 5 μM KN93 (calcium / calmodulin-dependent kinase inhibitor), or 10 μM HA1004 (protein kinase A inhibitor) in the presence or absence of 100 nM ADNF. After 72 hours of the transformation, cell mortality was measured by Trypan blue exclusion assay.

[0090]The results obtained using A4T-SOD1, G85R-SOD1, and G93R-SOD1 are respectively shown in FIGS. 3A to 3C.

[0091]The neuroprotective effect of ADNF was not affected by wortmannin (W), PD98059 (PD), SB203580 (SB), AG490 (AG), and HA1004 (HA), but it was inhibited by genistein (G) and KN93 (KN) (FIGS. 3A to 3C). This suggests that ADNF exerts its neuropr...

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Abstract

An object of the present invention is to provide an agent effective for the treatment and / or prevention of motor neuron disease such as amyotrophic lateral sclerosis (ALS). The present invention provides a therapeutic and / or preventive agent for motor neuron disease comprising the following oligopeptide shown in any of (a) to (c) or a pharmaceutically acceptable salt thereof as an active ingredient: (a) an oligopeptide consisting of the amino acid sequence represented by Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO: 1); (b) an oligopeptide consisting of an amino acid sequence having a deletion, substitution, insertion, or addition of one or several amino acids in Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO: 1), and having an activity that inhibits neuronal cell death caused by a mutant superoxide dismutase-1 gene; and (c) a modified oligopeptide from the oligopeptide (a) or (b).

Description

TECHNICAL FIELD[0001]The present invention relates to a therapeutic and / or preventive agent for motor neuron disease, particularly amyotrophic lateral sclerosis (ALS).BACKGROUND ART[0002]Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that typically affects people of middle or advanced ages and selectively attacks motor nerves in the cerebrum, brain stem, and spinal cord (Cleveland D W and Rothstein J D, 2001, Nat Rev Neurosci 2: 806-819; and Hand C K and Rouleau G A, 2002, Muscle Nerve 25: 135-159). ALS causes muscular atrophy and muscular weakness in voluntary muscles in the whole body except for extraocular muscle, and eventually respiratory failure. Most patients die in 3 to 5 years from the onset.[0003]Riluzole is the sole drug previously approved for ALS in US and Japan. Riluzole was originally developed as an anticonvulsant inhibiting glutamate release and has been reported in several clinical trials to exhibit only slight efficacy for the survival of ALS p...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/08A61P25/00A61K31/7088C07K19/00C07H21/04C12N15/63C12N1/21C12N1/19C12N5/10A61K38/00A61K38/16A61P25/02A61P25/28C07K7/06C07K14/47C12N1/15C12N15/09C12N15/12C12P21/02
CPCC07K14/47A61K38/16A61P21/04A61P25/00A61P25/02A61P25/28
Inventor AISO, SADAKAZUMATSUOKA, MASAAKICHIBA, TOMOHIROKITA, YOSHIKOTERASHITA, KENZO
Owner NOEVIR CO LTD
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