Therapeutic agent for amyotrophic lateral sclerosis and composition for treatment

A technology for lateral sclerosis and therapeutic agent, applied in the field of amyotrophic lateral sclerosis therapeutic agent and ALS therapeutic composition, can solve the problem that there is no ALS model, SOD1-ALS model cannot function as a model, and the drug Issues not yet developed

Pending Publication Date: 2019-06-04
KEIO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the wobbler variant is known not to be observed in ALS patients
[0004] In addition, SOD1 is known as one of the major causative genes of familial ALS, and transgenic mice (Non-Patent Document 2) into which mutant SOD1 has been introduced have been used in drug development research, but they have shown clear therapeutic effects in clinical practice medicines have not yet been developed
On the contrary, agents selected using the SOD1-ALS model do not show effectiveness in actual ALS patients in most cases. Currently, there is concern that the SOD1-ALS model may not be used as a model due to the separation of the SOD1-ALS model from clinical practice. and play a role
[0005] As such, no good ALS model has previously existed

Method used

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  • Therapeutic agent for amyotrophic lateral sclerosis and composition for treatment
  • Therapeutic agent for amyotrophic lateral sclerosis and composition for treatment
  • Therapeutic agent for amyotrophic lateral sclerosis and composition for treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0072] In one embodiment, the present invention provides a method for treating ALS, which includes the following steps: administering an effective amount of the compound represented by the above formula (1), its pharmaceutically acceptable salt, or their of solvates. In the treatment method of this embodiment, examples of the compound represented by the above formula (1), its pharmaceutically acceptable salt, or their solvate include the same ones as those described above.

[0073] In one embodiment, the present invention provides a compound represented by the above formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof for use in the treatment of ALS. In the treatment method of this embodiment, examples of the compound represented by the above formula (1), its pharmaceutically acceptable salt, or their solvate include the same ones as those described above.

[0074] In one embodiment, the present invention provides the use of the compound represented b...

experiment example I-1

[0078] (differentiate into motor neurons)

[0079] Among familial ALS, ALS due to mutation of FUS gene and ALS due to mutation of TDP-43 gene are known to exist.

[0080] Then, iPS cells derived from a healthy person, iPS cells derived from an ALS patient with a FUS mutation, and iPS cells derived from an ALS patient with a TDP-43 mutation were differentiated into motor neurons. The iPS cell lines used are as described in Table 1, all of which are derived from skin fibroblasts.

[0081] [Table 1]

[0082]

[0083] Specifically, first, each of the above cell lines was mixed with SB431542 (CAS number: 301836-41-9) at a final concentration of 3 μM, CHIR99021 (CAS number: 252917-06-9) at a final concentration of 3 μM, and Dorsomorphin (CAS number: 866405-64-3) at a concentration of 3 μM was cultured for 5 days to induce differentiation-promoted pluripotent stem cells (DiSC). Medium was exchanged daily. Hereinafter, the start of differentiation induction refers to the start ...

experiment example I-2

[0099] (Analysis of neurite length)

[0100] For each motor neuron induced to differentiate in Experimental Example I-1, the temporal change in neurite length was measured. Biostation CT (Nikon) was used for the temporal measurement of neurite length. figure 1 is a graph showing the measurement results of neurite length changes over time. The vertical axis shows neurite length (relative value), and the horizontal axis shows the number of days of culture from the initiation of differentiation induction. As a result, it was clarified that in motor neurons induced by differentiation of iPS cells derived from healthy individuals, neurite length continued to extend, whereas in motor neurons induced by differentiation of iPS cells derived from ALS patients, The neurite length which is the peak at about day 40 from the initiation of differentiation induction shortens. The results show that differentiation-induced motor neurons reflect the pathology of ALS.

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Abstract

The invention provides a therapeutic agent for amyotrophic lateral sclerosis, comprising: a compound represented by formula (1) (in formula (1), R1 each independently represents an alkyl group containing 1-6 carbon atoms or a 4-hydroxyphenethyl group, and n represents an integer of 1-3); a pharmacologically acceptable salt thereof; or a solvate of the compound and the salt, as an effective ingredient.

Description

technical field [0001] The present invention relates to an amyotrophic lateral sclerosis (Amyotrophic Lateral Sclerosis, ALS) therapeutic agent and a composition for ALS treatment. This application claims priority based on Japanese Patent Application No. 2016-172255 for which it applied in Japan on September 2, 2016, and uses the content here. Background technique [0002] ALS is a neurodegenerative disease that causes severe muscle atrophy and decreased muscle strength, and is a type of motor neuron disease. In ALS, motor neuron-specific lesions are observed, showing extremely rapid disease (morbidity) progression with a mean survival time of several years after onset. For ALS, there is no effective treatment method, and it is desired to develop a therapeutic agent as soon as possible. Although most cases of ALS are sporadic, 10% of patients are familial with a clear genetic component. [0003] A mutant mouse called a wobbler mouse has been used as an ALS model because i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/404A61P21/00
CPCA61K31/404A61P21/00A61P25/00
Inventor 冈野荣之藤森康希奥野博庸
Owner KEIO UNIV
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