Agent for suppressing aggregation of TDP-43, agent for suppressing cell death of cells in which TDP-43 is overexpressed, and agent for preventing or treating diseases associated with aggregation of TDP-43

Abstract

An agent for suppressing aggregation of TDP-43 that includes a combination of: at least one selected from the group consisting of cycloserine, terizidone, and salts thereof; and edaravone. An agent for suppressing aggregation of TDP-43 that includes at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, used in combination with edaravone. An agent for suppressing aggregation of TDP-43 that includes edaravone used in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

Description

Inhibitor of TDP-43 aggregation, inhibitor of cell death in cells overexpressing TDP-43, and therapeutic or preventive agent for diseases associated with TDP-43 aggregation

[0001] The present invention relates to an inhibitor of TDP-43 aggregation, an inhibitor of cell death of cells in which TDP-43 is overexpressed, and an agent for treating or preventing diseases associated with TDP-43 aggregation.

[0002] TDP-43 (TAR DNA-binding protein of 43 kDa) is a heterogeneous nuclear ribonucleoprotein. TDP-43 has been identified as a major component of ubiquitin-positive inclusions that appear in degenerated neurons and glial cells in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 is a nuclear-localized protein, but in cells in which ubiquitin-positive inclusions are formed, TDP-43 translocates from the nucleus to the cytoplasm, aggregates, becomes insoluble, and accumulates in the cytoplasm.

[0003] TDP-43, which accumulates in the brains and spinal cords of ALS and FTLD patients, is abnormally phosphorylated at multiple serine residues at its C-terminus. In ALS and FTLD patients, it is not necessary for the full-length TDP-43 molecule to aggregate; rather, C-terminal fragments of TDP-43 aggregate. Research to date has strongly suggested that TDP-43 aggregation causes abnormalities in RNA metabolism and induces cytotoxicity, leading to the onset and progression of various diseases.

[0004] An example of a disease associated with TDP-43 aggregation is TDP-43 proteinopathy. Patent Document 1 proposes the use of N,N,N',N',-tetramethyl-10H-phenothiazine-3,7-diaminium bis(methanesulfonate) as a therapeutic or preventive agent for TDP-43 proteinopathy.

[0005] Patent No. 5898701

[0006] An object of the present invention is to provide an inhibitor of TDP-43 aggregation, an inhibitor of cell death of cells in which TDP-43 is overexpressed, and an agent for treating or preventing diseases accompanied by TDP-43 aggregation.

[0007] According to an aspect of the present invention, there is provided an inhibitor of TDP-43 aggregation or an inhibitor of cell death of cells in which TDP-43 is overexpressed, comprising a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0008] In the above-mentioned inhibitor of TDP-43 aggregation or inhibitor of cell death of cells in which TDP-43 is overexpressed, the active ingredient may essentially consist of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0009] In the present disclosure, "consisting essentially of" means that the active ingredient does not contain any other ingredients, and does not exclude the presence of ingredients other than the active ingredient, such as excipients and / or lubricants.

[0010] In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, the active ingredient may be a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0011] In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0012] In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, the cycloserine may be D-cycloserine.In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, the cycloserine may be L-cycloserine.

[0013] The inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed may contain at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

[0014] The inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed may contain 30 mg or more and 60 mg or less of edaravone.

[0015] The inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed may not contain acamprosate.

[0016] According to an aspect of the present invention, there is provided a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and a salt thereof for use in inhibiting TDP-43 aggregation or inhibiting cell death of cells in which TDP-43 is overexpressed.

[0017] In the above combination, the active ingredients may consist essentially of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0018] In the above combination, the active ingredients may be a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0019] In the above combination, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0020] In the above combination, the cycloserine may be D-cycloserine.In the above combination, the cycloserine may be L-cycloserine.

[0021] The above combination may contain at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine and terizidone, and salts thereof.

[0022] The above combination may contain 30 mg or more and 60 mg or less of edaravone.

[0023] The above combinations may not include acamprosate.

[0024] According to an aspect of the present invention, there is provided use of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof for the manufacture of an inhibitor of TDP-43 aggregation or an inhibitor of cell death of cells in which TDP-43 is overexpressed.

[0025] In the above-mentioned use, the active ingredient of the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed may consist essentially of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0026] In the above-mentioned use, the active ingredient of the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed may consist of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0027] In the above use, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0028] In the above use, the cycloserine may be D-cycloserine.In the above use, the cycloserine may be L-cycloserine.

[0029] In the above use, the combination may contain at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine and terizidone, and salts thereof.

[0030] In the above use, the combination may contain 30 mg or more and 60 mg or less of edaravone.

[0031] In the above uses, the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed may not contain acamprosate.

[0032] According to an aspect of the present invention, there is provided a method for suppressing TDP-43 aggregation in a subject or a method for suppressing cell death of cells in which TDP-43 is overexpressed in a subject, the method comprising administering to the subject a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and a salt thereof.

[0033] In the above-mentioned method for inhibiting TDP-43 aggregation or method for inhibiting cell death of cells in which TDP-43 is overexpressed, the active ingredient for inhibiting TDP-43 aggregation may consist essentially of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0034] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, the active ingredient for inhibiting TDP-43 aggregation may comprise a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0035] In the above-mentioned method for inhibiting TDP-43 aggregation or method for inhibiting cell death of cells in which TDP-43 is overexpressed, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0036] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, cycloserine may be D-cycloserine.In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, cycloserine may be L-cycloserine.

[0037] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, the single dose of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 15 mg or more and less than 250 mg.

[0038] In the method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, the single dose of edaravone may be 30 mg or more and 60 mg or less.

[0039] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, acamprosate does not need to be administered to the subject.

[0040] According to an aspect of the present invention, there is provided an inhibitor of TDP-43 aggregation or an inhibitor of cell death of cells in which TDP-43 is overexpressed, comprising at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, in combination with edaravone.

[0041] In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may not be used in combination with any active ingredient other than edaravone.

[0042] In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0043] In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, the cycloserine may be D-cycloserine.In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, the cycloserine may be L-cycloserine.

[0044] The inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed may contain at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

[0045] In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be used in combination with 30 mg or more and 60 mg or less of edaravone.

[0046] The inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed may not contain acamprosate.

[0047] According to an aspect of the present invention, there is provided at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, in combination with edaravone for use in inhibiting TDP-43 aggregation or inhibiting cell death of cells in which TDP-43 is overexpressed.

[0048] At least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be used in combination with no active ingredient other than edaravone.

[0049] At least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0050] In at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, the cycloserine may be D-cycloserine.In at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, the cycloserine may be L-cycloserine.

[0051] The mass of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 15 mg or more and less than 250 mg.

[0052] The mass of edaravone used in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 30 mg or more and less than 60 mg.

[0053] The above-mentioned edaravone does not need to be used in combination with acamprosate.

[0054] According to an aspect of the present invention, there is provided use of at least one selected from the group consisting of cycloserine and terizidone, and salts thereof, in combination with edaravone for the manufacture of an inhibitor of TDP-43 aggregation or an inhibitor of cell death of cells in which TDP-43 is overexpressed.

[0055] In the above use, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be used in combination with no active ingredient other than edaravone.

[0056] In the above use, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0057] In the above use, the cycloserine may be D-cycloserine.In the above use, the cycloserine may be L-cycloserine.

[0058] In the above use, the mass of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 15 mg or more and less than 250 mg.

[0059] In the above use, the mass of edaravone used in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 30 mg or more and less than 60 mg.

[0060] In the above use, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may not be used in combination with acamprosate.

[0061] According to an aspect of the present invention, there is provided a method for suppressing TDP-43 aggregation in a subject, or a method for suppressing cell death of cells in which TDP-43 is overexpressed in a subject, comprising administering to the subject at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, in combination with edaravone.

[0062] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may not be used in combination with any active ingredient other than edaravone.

[0063] In the above-mentioned method for inhibiting TDP-43 aggregation or method for inhibiting cell death of cells in which TDP-43 is overexpressed, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0064] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, cycloserine may be D-cycloserine.In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, cycloserine may be L-cycloserine.

[0065] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, the single dose of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 15 mg or more and less than 250 mg.

[0066] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be used in combination with 30 mg or more and 60 mg or less of edaravone.

[0067] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, acamprosate does not need to be administered to the subject.

[0068] According to an aspect of the present invention, there is provided an inhibitor of TDP-43 aggregation or an inhibitor of cell death in cells in which TDP-43 is overexpressed, comprising edaravone in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0069] In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, edaravone may not be used in combination with at least one active ingredient other than cycloserine, terizidone, and salts thereof.

[0070] In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0071] In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, the cycloserine may be D-cycloserine.In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, the cycloserine may be L-cycloserine.

[0072] In the inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed, edaravone may be used in combination with at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

[0073] The inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed may contain 30 mg or more and 60 mg or less of edaravone.

[0074] The inhibitor of TDP-43 aggregation or the inhibitor of cell death of cells in which TDP-43 is overexpressed may not contain acamprosate.

[0075] According to an aspect of the present invention, there is provided edaravone in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, for use in inhibiting TDP-43 aggregation or inhibiting cell death of cells in which TDP-43 is overexpressed.

[0076] The above-mentioned edaravone may not be used in combination with any other active ingredient than at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0077] At least one selected from the group consisting of cycloserine, terizidone, and salts thereof used in combination with edaravone may be cycloserine or a salt thereof.

[0078] The cycloserine used in combination with edaravone may be D-cycloserine. The cycloserine used in combination with edaravone may be L-cycloserine.

[0079] The above-mentioned edaravone may be used in combination with at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

[0080] The mass of the edaravone may be 30 mg or more and 60 mg or less.

[0081] At least one selected from the group consisting of cycloserine, terizidone, and salts thereof, which are used in combination with edaravone, does not necessarily have to be used in combination with acamprosate.

[0082] According to an aspect of the present invention, there is provided use of edaravone in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, for the manufacture of an inhibitor of TDP-43 aggregation or an inhibitor of cell death of cells in which TDP-43 is overexpressed.

[0083] In the above use, edaravone may not be used in combination with at least one active ingredient other than cycloserine, terizidone, and salts thereof.

[0084] In the above use, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0085] In the above use, the cycloserine may be D-cycloserine.In the above use, the cycloserine may be L-cycloserine.

[0086] In the above use, the mass of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof used in combination with edaravone may be 15 mg or more and less than 250 mg.

[0087] In the above use, the mass of edaravone may be 30 mg or more and less than 60 mg.

[0088] In the above use, edaravone does not have to be used in combination with acamprosate.

[0089] According to an aspect of the present invention, there is provided a method for suppressing TDP-43 aggregation in a subject or a method for suppressing cell death of cells in which TDP-43 is overexpressed in a subject, the method comprising administering edaravone in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof to the subject.

[0090] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, edaravone may not be used in combination with any other active ingredient than at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0091] In the above-mentioned method for inhibiting TDP-43 aggregation or method for inhibiting cell death of cells in which TDP-43 is overexpressed, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0092] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, cycloserine may be D-cycloserine.In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, cycloserine may be L-cycloserine.

[0093] In the method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, the single dose of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, used in combination with edaravone may be 15 mg or more and less than 250 mg.

[0094] In the method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, the single dose of edaravone may be 30 mg or more and less than 60 mg.

[0095] In the above-mentioned method for inhibiting TDP-43 aggregation or the method for inhibiting cell death of cells in which TDP-43 is overexpressed, acamprosate does not need to be administered to the subject.

[0096] According to an aspect of the present invention, there is provided an agent for treating or preventing a disease associated with TDP-43 aggregation, comprising a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and a salt thereof.

[0097] In the above-mentioned agent for treating or preventing a disease accompanied by aggregation of TDP-43, the active ingredient may consist essentially of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0098] In the above-mentioned agent for treating or preventing a disease accompanied by aggregation of TDP-43, the active ingredient may consist of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0099] In the above-mentioned agent for treating or preventing a disease accompanied by aggregation of TDP-43, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0100] In the above-mentioned agent for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be D-cycloserine. In the above-mentioned agent for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be L-cycloserine.

[0101] In the above-mentioned agent for treating or preventing a disease accompanied by TDP-43 aggregation, the disease accompanied by TDP-43 aggregation may be TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0102] The therapeutic or prophylactic agent for a disease accompanied by aggregation of TDP-43 may contain at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

[0103] The therapeutic or preventive agent for a disease accompanied by aggregation of TDP-43 may contain 30 mg or more and 60 mg or less of edaravone.

[0104] The above-mentioned therapeutic or preventive agent for a disease associated with TDP-43 aggregation may not contain acamprosate.

[0105] According to an aspect of the present invention, there is provided a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof for use in the treatment or prevention of a disease associated with TDP-43 aggregation.

[0106] In the above combination, the active ingredients may consist essentially of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0107] In the above combination, the active ingredients may be a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0108] In the above combination, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0109] In the above combination, the cycloserine may be D-cycloserine.In the above combination, the cycloserine may be L-cycloserine.

[0110] In the above combination, the disease associated with TDP-43 aggregation may be a TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0111] The above combination may contain at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine and terizidone, and salts thereof.

[0112] The above combination may contain 30 mg or more and 60 mg or less of edaravone.

[0113] The above combinations may not include acamprosate.

[0114] According to an aspect of the present invention, there is provided use of a combination of at least one selected from the group consisting of cycloserine, terizidone, and a salt thereof, and edaravone, for the manufacture of an agent for treating or preventing a disease associated with TDP-43 aggregation.

[0115] In the above-mentioned use, the active ingredient of the therapeutic or preventive agent for a disease associated with TDP-43 aggregation may consist essentially of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0116] In the above use, the active ingredient of the therapeutic or preventive agent for a disease associated with TDP-43 aggregation may consist of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0117] In the above use, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0118] In the above use, the cycloserine may be D-cycloserine.In the above use, the cycloserine may be L-cycloserine.

[0119] In the above use, the disease associated with TDP-43 aggregation may be a TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0120] In the above use, the combination may contain at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine and terizidone, and salts thereof.

[0121] In the above use, the combination may contain 30 mg or more and 60 mg or less of edaravone.

[0122] In the above uses, the combination may not include acamprosate.

[0123] According to an aspect of the present invention, there is provided a method for treating or preventing a disease associated with TDP-43 aggregation in a subject, the method comprising administering to the subject a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and a salt thereof.

[0124] In the above-mentioned method for treating or preventing a disease accompanied by aggregation of TDP-43, the active ingredient that inhibits aggregation of TDP-43 may consist essentially of a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0125] In the above-mentioned method for treating or preventing a disease accompanied by aggregation of TDP-43, the active ingredient that inhibits aggregation of TDP-43 may comprise a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0126] In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0127] In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be D-cycloserine. In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be L-cycloserine.

[0128] In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, the disease accompanied by TDP-43 aggregation may be a TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0129] In the method for treating or preventing a disease accompanied by TDP-43 aggregation, the single dose of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 15 mg or more and less than 250 mg.

[0130] In the method for treating or preventing a disease accompanied by TDP-43 aggregation, the single dose of edaravone may be 30 mg or more and 60 mg or less.

[0131] In the above-mentioned method for treating or preventing a disease associated with TDP-43 aggregation, acamprosate may not be administered to the subject.

[0132] According to an aspect of the present invention, there is provided an agent for treating or preventing a disease associated with TDP-43 aggregation, comprising at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, in combination with edaravone.

[0133] In the above-mentioned agent for treating or preventing a disease accompanied by aggregation of TDP-43, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may not be used in combination with any active ingredient other than edaravone.

[0134] In the above-mentioned agent for treating or preventing a disease accompanied by aggregation of TDP-43, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0135] In the above-mentioned agent for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be D-cycloserine. In the above-mentioned agent for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be L-cycloserine.

[0136] In the above-mentioned agent for treating or preventing a disease accompanied by TDP-43 aggregation, the disease accompanied by TDP-43 aggregation may be TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0137] The therapeutic or prophylactic agent for a disease accompanied by aggregation of TDP-43 may contain at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

[0138] In the above-mentioned agent for treating or preventing a disease accompanied by aggregation of TDP-43, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be used in combination with 30 mg or more and 60 mg or less of edaravone.

[0139] The above-mentioned therapeutic or preventive agent for a disease associated with TDP-43 aggregation may not contain acamprosate.

[0140] According to an aspect of the present invention, there is provided at least one selected from the group consisting of cycloserine and terizidone, and salts thereof, in combination with edaravone for use in treating or preventing a disease associated with TDP-43 aggregation.

[0141] At least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be used in combination with no active ingredient other than edaravone.

[0142] At least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0143] In at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, the cycloserine may be D-cycloserine.In at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, the cycloserine may be L-cycloserine.

[0144] In the above-mentioned at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, the disease accompanied by TDP-43 aggregation may be a TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0145] The mass of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 15 mg or more and less than 250 mg.

[0146] The mass of edaravone used in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 30 mg or more and less than 60 mg.

[0147] At least one selected from the group consisting of cycloserine, terizidone, and salts thereof may not be used in combination with acamprosate.

[0148] According to an aspect of the present invention, there is provided use of at least one selected from the group consisting of cycloserine and terizidone, and salts thereof, in combination with edaravone for the manufacture of an agent for treating or preventing a disease associated with TDP-43 aggregation.

[0149] In the above use, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be used in combination with no active ingredient other than edaravone.

[0150] In the above use, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0151] In the above use, the cycloserine may be D-cycloserine.In the above use, the cycloserine may be L-cycloserine.

[0152] In the above use, the disease associated with TDP-43 aggregation may be a TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0153] In the above use, the mass of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 15 mg or more and less than 250 mg.

[0154] In the above use, the mass of edaravone used in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 30 mg or more and less than 60 mg.

[0155] In the above use, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may not be used in combination with acamprosate.

[0156] According to an aspect of the present invention, there is provided a method for treating or preventing a disease associated with TDP-43 aggregation in a subject, the method comprising administering to the subject at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, in combination with edaravone.

[0157] In the above-mentioned method for treating or preventing a disease accompanied by aggregation of TDP-43, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may not be used in combination with any active ingredient other than edaravone.

[0158] In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0159] In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be D-cycloserine. In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be L-cycloserine.

[0160] In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, the disease accompanied by TDP-43 aggregation may be a TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0161] In the method for treating or preventing a disease accompanied by TDP-43 aggregation, the single dose of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be 15 mg or more and less than 250 mg.

[0162] In the above-mentioned method for treating or preventing a disease accompanied by aggregation of TDP-43, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be used in combination with 30 mg or more and 60 mg or less of edaravone.

[0163] In the above-mentioned method for treating or preventing a disease associated with TDP-43 aggregation, acamprosate may not be administered to the subject.

[0164] According to an aspect of the present invention, there is provided an agent for treating or preventing a disease associated with TDP-43 aggregation, comprising edaravone in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0165] In the above-mentioned agent for treating or preventing a disease accompanied by aggregation of TDP-43, edaravone may not be used in combination with any other active ingredient than at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0166] In the above-mentioned agent for treating or preventing a disease accompanied by aggregation of TDP-43, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0167] In the above-mentioned agent for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be D-cycloserine. In the above-mentioned agent for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be L-cycloserine.

[0168] In the above-mentioned agent for treating or preventing a disease accompanied by TDP-43 aggregation, the disease accompanied by TDP-43 aggregation may be TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0169] In the above-mentioned agent for treating or preventing a disease accompanied by aggregation of TDP-43, edaravone may be used in combination with at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

[0170] The therapeutic or preventive agent for a disease accompanied by aggregation of TDP-43 may contain 30 mg or more and 60 mg or less of edaravone.

[0171] The above-mentioned therapeutic or preventive agent for a disease associated with TDP-43 aggregation may not contain acamprosate.

[0172] According to an aspect of the present invention, there is provided edaravone in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, for use in treating or preventing a disease associated with TDP-43 aggregation.

[0173] The above-mentioned edaravone may not be used in combination with any other active ingredient than at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0174] At least one selected from the group consisting of cycloserine, terizidone, and salts thereof used in combination with edaravone may be cycloserine or a salt thereof.

[0175] The cycloserine used in combination with edaravone may be D-cycloserine. The cycloserine used in combination with edaravone may be L-cycloserine.

[0176] In the above-mentioned edaravone, the disease accompanied by TDP-43 aggregation may be a TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0177] The above-mentioned edaravone may be used in combination with at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

[0178] The mass of the edaravone may be 30 mg or more and 60 mg or less.

[0179] The above-mentioned edaravone does not need to be used in combination with acamprosate.

[0180] According to an aspect of the present invention, there is provided use of edaravone in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, for the manufacture of an agent for treating or preventing a disease associated with TDP-43 aggregation.

[0181] In the above use, edaravone may not be used in combination with at least one active ingredient other than cycloserine, terizidone, and salts thereof.

[0182] In the above use, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0183] In the above use, the cycloserine may be D-cycloserine.In the above use, the cycloserine may be L-cycloserine.

[0184] In the above use, the disease associated with TDP-43 aggregation may be a TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0185] In the above use, the mass of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof used in combination with edaravone may be 15 mg or more and less than 250 mg.

[0186] In the above use, the mass of edaravone may be 30 mg or more and less than 60 mg.

[0187] In the above use, edaravone may not be used in combination with acamprosate.

[0188] According to an aspect of the present invention, there is provided a method for treating or preventing a disease associated with TDP-43 aggregation in a subject, the method comprising administering edaravone in combination with at least one selected from the group consisting of cycloserine and terizidone, and salts thereof, to the subject.

[0189] In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, edaravone may not be used in combination with any other active ingredient than at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0190] In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, at least one selected from the group consisting of cycloserine, terizidone, and salts thereof may be cycloserine or a salt thereof.

[0191] In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be D-cycloserine. In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, cycloserine may be L-cycloserine.

[0192] In the above-mentioned method for treating or preventing a disease accompanied by TDP-43 aggregation, the disease accompanied by TDP-43 aggregation may be a TDP-43 proteinopathy. The TDP-43 proteinopathy may be at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular atrophy. The TDP-43 proteinopathy may be amyotrophic lateral sclerosis.

[0193] In the method for treating or preventing a disease accompanied by TDP-43 aggregation, the single dose of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, used in combination with edaravone may be 15 mg or more and less than 250 mg.

[0194] In the method for treating or preventing a disease accompanied by TDP-43 aggregation, the single dose of edaravone may be 30 mg or more and less than 60 mg.

[0195] In the above-mentioned method for treating or preventing a disease associated with TDP-43 aggregation, acamprosate may not be administered to the subject.

[0196] According to the present invention, it is possible to provide an inhibitor of TDP-43 aggregation, an inhibitor of cell death of cells in which TDP-43 is overexpressed, and an agent for treating or preventing diseases accompanied by TDP-43 aggregation.

[0197] FIG. 1 is a photograph showing the soluble fraction of TDP-43 and the insoluble fraction of TDP-43 according to Reference Example 1. FIG. 2 is a graph showing the relationship between the time elapsed since transfection of the TDP-43 gene and the proportion of the insoluble fraction of TDP-43 in cells according to Reference Example 1. FIG. 3 is a photograph of cells according to Reference Example 2. FIG. 4 is a graph showing the relationship between the concentration of a compound according to Reference Example 2 and the relative viability of cells. FIG. 5 is a photograph showing the soluble fraction of TDP-43 and the insoluble fraction of TDP-43 according to Reference Example 3. FIG. 6 is a graph showing the relationship between the compound according to Reference Example 3 and the proportion of the insoluble fraction of TDP-43 in cells. FIG. 7 is a photograph showing the soluble fraction of TDP-43 and the insoluble fraction of TDP-43 according to Reference Example 4. FIG. 8 is a graph showing the proportion of the insoluble fraction of TDP-43 according to Reference Example 4. 9 is a graph showing the relationship between the concentration of the compound according to Example 1 and the relative survival rate of cells. FIG. 10 is a graph showing the EC of the cell death inhibitory effect of D-cycloserine for each concentration of edaravone according to Example 1. 50 11 is a graph showing the EC of the cell death inhibitory effect of D-cycloserine at different concentrations of edaravone in Example 1. 50 and the combination index values.

[0198] The following describes embodiments of the present invention. However, it should not be understood that the following embodiments limit the present invention. From this disclosure, various alternative embodiments, examples, and operating techniques will become apparent to those skilled in the art. It should be understood that the present invention encompasses various embodiments not described herein.

[0199] According to the embodiments, an agent for treating or preventing a disease accompanied by aggregation of TDP-43 (TAR DNA-binding protein of 43 kDa), an inhibitor of TDP-43 aggregation, or an inhibitor of cell death of cells in which TDP-43 is overexpressed comprises a combination of at least one selected from the group consisting of cycloserine and physiologically acceptable salts thereof, and edaravone.

[0200] Furthermore, the therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the inhibitor of cell death of cells in which TDP-43 is overexpressed according to the embodiments comprises at least one selected from the group consisting of cycloserine and physiologically acceptable salts thereof, used in combination with edaravone.

[0201] Furthermore, the therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the inhibitor of cell death of cells in which TDP-43 is overexpressed according to the embodiments comprises edaravone in combination with at least one selected from the group consisting of cycloserine and physiologically acceptable salts thereof.

[0202] Examples of diseases involving aggregation of TDP-43 include TDP-43 proteinopathies, neurodegenerative diseases, and muscle diseases.

[0203] Examples of TDP-43 proteinopathies include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), primary lateral sclerosis (PLS), and progressive muscular atrophy (PMA). Frontotemporal lobar degeneration (FTLD) may be frontotemporal lobar degeneration associated with TDP-43 accumulation (FTLD-TDP).

[0204] Examples of neurodegenerative diseases include dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Guam-type ALS / Parkinson's complex dementia, hippocampal sclerosis, Pick's disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, argyrophilic grain disease (AGD), chronic traumatic encephalopathy (CTE), multiple system atrophy (MSA), and limbic age-related TDP-43 encephalopathy.

[0205] Examples of muscle diseases include inclusion body myopathy with Paget's disease of bone and frontotemporal dementia, sporadic IBM, myofibrillar myopathy, oculopharyngeal muscular dystrophy, and distal myopathy with rimmed vacuoles.

[0206] The cycloserine may be D-cycloserine or L-cycloserine.

[0207] The IUPAC name of D-cycloserine (CAS number: 68-41-7) is (4R)-4-Amino-1,2-oxazolidin-3-one. The chemical formula of D-cycloserine is C3H6N2O2. The chemical structural formula of D-cycloserine is as follows:

[0208] The IUPAC name of L-cycloserine (CAS number: 339-72-0) is (4S)-4-amino-1,2-oxazolidin-3-one. The chemical formula of L-cycloserine is C3H6N2O2. The chemical structural formula of L-cycloserine is as follows:

[0209] The IUPAC name of edaravone (CAS number: 89-25-8) is 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one. The chemical formula of edaravone is C 10 H 10 NO. The chemical structure of edaravone is as follows:

[0210] The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the inhibitor of cell death of cells in which TDP-43 is overexpressed according to the embodiments may contain at least one prodrug of the above-mentioned compound or a physiologically acceptable salt thereof.

[0211] For example, terizidone is known as a prodrug of D-cycloserine. The IUPAC name of terizidone (CAS number: 25683-71-0) is 4,4'-{1,4-phenylenebis[(E)methylylidene(E)azanylylidene]}bis(1,2-oxazolidin-3-one). The chemical formula of terizidone is C 14 H 14 N4O4. The chemical structure of terizidone is: Terizidone is broken down in the body and exerts effects similar to those of D-cycloserine.

[0212] According to the embodiments, the therapeutic or preventive agent for a disease associated with TDP-43 aggregation, the TDP-43 aggregation inhibitor, or the inhibitor of cell death of cells in which TDP-43 is overexpressed can be formulated into a pharmaceutically acceptable dosage form. For example, the therapeutic or preventive agent for a disease associated with TDP-43 aggregation, the TDP-43 aggregation inhibitor, or the inhibitor of cell death of cells in which TDP-43 is overexpressed can be formulated into an injection, a solution, a suspension, a tablet, a capsule, a pill, a granule, a syrup, a suppository, an inhalant, or a spray. Injectable agents include, for example, an injection solution, a sterile powder for injection, and a concentrated solution for injection.

[0213] The maximum blood concentration (Cmax) of D-cycloserine following oral administration of 15 mg of D-cycloserine to humans has been reported to be approximately 5.6 μmol / L (van Berckel, B., Lipsch, C., Timp, S. et al. Behavioral and Neuroendocrine Effects of the Partial NMDA Agonist D-cycloserine in Healthy Subjects. Neuropsychopharmacol 16, 317-324 (1997). https: / / doi.org / 10.1016 / S0893-133X(96)00196-0, and van Berckel, B. Erratum: Behavioral and Neuroendocrine Effects of the Partial NMDA Agonist D-cycloserine in Healthy Subjects. Neuropsychopharmacol 17, 116 (1997). https: / / doi.org / 10.1016 / S0893-133X(97)00082-1).

[0214] The rate of D-cycloserine transfer into the brain has been reported to be 95%. Therefore, the maximum concentration of D-cycloserine in the brain is estimated to be approximately 5.3 μmol / L. This concentration of approximately 5.3 μmol / L is the EC value of D-cycloserine that suppresses cell death in neurons forced to express TDP-43, as shown in Reference Example 2 below. ５０The trough value of 15 mg of D-cycloserine administered orally twice daily exceeds EC200 / C128 nmol / L. ５０ Therefore, the therapeutic or preventive agent for diseases accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the inhibitor of cell death of cells in which TDP-43 is overexpressed according to the embodiments can sufficiently exert therapeutic or preventive effects for diseases accompanied by TDP-43 aggregation, such as human amyotrophic lateral sclerosis, by containing 15 mg or more of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0215] Furthermore, it has been reported that when D-cycloserine is administered to humans at a dose of 250 mg for the treatment of tuberculosis, it causes serious side effects such as epileptiform convulsions and mental confusion. Therefore, the therapeutic or preventive agent for diseases accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the inhibitor of cell death of cells in which TDP-43 is overexpressed according to the embodiments contains less than 250 mg of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, thereby making it possible to suppress side effects caused by at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0216] It has been reported that administration of 150 mg of D-cycloserine to humans causes headache. However, since diseases accompanied by TDP-43 aggregation, such as amyotrophic lateral sclerosis, are extremely serious, treatment should be prioritized even if headache occurs as a side effect.

[0217] The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the inhibitor of cell death of cells in which TDP-43 is overexpressed according to the embodiments may contain, for example, 17 mg or more, 20 mg or more, or 25 mg or more of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

[0218] The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the inhibitor of cell death of cells in which TDP-43 is overexpressed according to the embodiments may contain at least one selected from the group consisting of cycloserine and terizidone, and salts thereof, in an amount of, for example, 249.9 mg or less, 249 mg or less, 240 mg or less, 230 mg or less, 220 mg or less, 210 mg or less, 200 mg or less, 190 mg or less, 180 mg or less, 170 mg or less, 160 mg or less, 150 mg or less, 100 mg or less, 80 mg or less, or 60 mg or less.

[0219] The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the inhibitor of cell death of cells in which TDP-43 is overexpressed according to the embodiments contains at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof, and the administered at least one selected from the group consisting of cycloserine and salts thereof acts in an agonist-like manner on the NMDA receptor.

[0220] According to the embodiments, the therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the TDP-43 aggregation inhibitor, or the inhibitor of cell death of cells in which TDP-43 is overexpressed contains, for example, 30 mg or more and 60 mg or less of edaravone. According to the embodiments, the therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the TDP-43 aggregation inhibitor, or the inhibitor of cell death of cells in which TDP-43 is overexpressed contains, for example, 30 mg or more and 60 mg or less of edaravone, thereby enabling the efficacy of edaravone to be exerted while suppressing side effects of edaravone. Side effects of edaravone include liver dysfunction and rash. According to the embodiments, the therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the TDP-43 aggregation inhibitor, or the inhibitor of cell death of cells in which TDP-43 is overexpressed may contain, for example, 32 mg or more, 34 mg or more, or 36 mg or more of edaravone. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the inhibitor of cell death of cells in which TDP-43 is overexpressed according to the embodiments may contain, for example, 58 mg or less, 56 mg or less, or 54 mg or less of edaravone.

[0221] The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the inhibitor of cell death of cells in which TDP-43 is overexpressed according to the embodiments may contain a mixture of at least one selected from the group consisting of cycloserine and physiologically acceptable salts thereof, and edaravone. The at least one selected from the group consisting of cycloserine and physiologically acceptable salts thereof and edaravone may be formulated together. Alternatively, in the therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation, the inhibitor of TDP-43 aggregation, or the inhibitor of cell death of cells in which TDP-43 is overexpressed according to the embodiments, the at least one selected from the group consisting of cycloserine and physiologically acceptable salts thereof and edaravone may be formulated separately.

[0222] At least one selected from the group consisting of cycloserine and a physiologically acceptable salt thereof and edaravone can be used in combination therapy. At least one selected from the group consisting of cycloserine and a physiologically acceptable salt thereof and edaravone can be administered to a subject simultaneously or at different times. At least one selected from the group consisting of cycloserine and a physiologically acceptable salt thereof can be administered to a subject first, and edaravone can be administered to the subject minutes, hours, or days later. Edaravone can be administered to a subject first, and at least one selected from the group consisting of cycloserine and a physiologically acceptable salt thereof can be administered to the subject minutes, hours, or days later.

[0223] As described above, it has been strongly suggested that TDP-43 aggregation causes abnormalities in RNA metabolism and cytotoxicity, leading to the onset and progression of various diseases. The therapeutic or preventive agent for diseases accompanied by TDP-43 aggregation according to the embodiment is capable of treating or preventing diseases accompanied by TDP-43 aggregation by inhibiting TDP-43 aggregation. Alternatively, the therapeutic or preventive agent for diseases accompanied by TDP-43 aggregation according to the embodiment is capable of treating or preventing diseases accompanied by TDP-43 aggregation by inhibiting cell death of cells in which TDP-43 is overexpressed.

[0224] According to embodiments, the therapeutic or preventive agent for diseases associated with TDP-43 aggregation, the TDP-43 aggregation inhibitor, or the inhibitor of cell death in cells in which TDP-43 is overexpressed may not contain acamprosate. Acamprosate is a derivative of homotaurine and is also known as 3-(acetylamino)propylsulfonic acid or N-acetylhomotaurine. Administration of acamprosate to humans may cause anaphylaxis accompanied by symptoms such as generalized rash, hives, stomatitis, laryngeal spasm, and shortness of breath as a side effect. Furthermore, administration of acamprosate to humans may cause angioedema accompanied by symptoms such as tongue swelling and lymphadenopathy as a side effect. According to embodiments, the therapeutic or preventive agent for diseases associated with TDP-43 aggregation, the TDP-43 aggregation inhibitor, or the inhibitor of cell death in cells in which TDP-43 is overexpressed does not need to be combined with acamprosate, and therefore does not cause these side effects.

[0225] Although the present invention has been described above by way of the embodiments, the descriptions and drawings that form part of this disclosure should not be understood to limit the present invention. From this disclosure, various alternative embodiments, examples, and operating techniques will become apparent to those skilled in the art. It should be understood that the present invention encompasses various embodiments not described herein.

[0226] (Reference Example 1) Mouse neuroblastoma (Neuro2a) cells were seeded onto a dish. Neuro2a cells were cultured in a DMEM + 10% FBS medium at 37°C in the presence of 5% CO2. One day after seeding, differentiation into neurons was initiated. Neuronal differentiation was carried out in a DMEM + 2% FBS + 20 μmol / L retinoic acid medium. Four days after seeding, the cells were transfected with synthesized TDP-43 mRNA by lipofection. Cells were sampled 6, 9, 12, 15, 18, and 21 hours after transfection. Cell death was observed 21 hours after transfection. For sampling, cells were lysed in RIPA buffer and centrifuged at 22,000 x g for 30 minutes at 4°C. The supernatant was used as the soluble fraction, and the precipitate was used as the insoluble fraction. An equal volume of 2x SDS sample buffer was added to each, and the mixture was heated at 95°C for 5 minutes to prepare electrophoresis samples. Each electrophoresis sample was subjected to electrophoresis using a polyacrylamide gel, after which TDP-43 was transferred to a PVDF membrane. TDP-43 was detected by chemiluminescence using an anti-TDP-43 antibody as the primary antibody and an HRP-conjugated anti-rabbit antibody as the secondary antibody. The results are shown in Figures 1 and 2. It was confirmed that the insoluble fraction of TDP-43 increased in cells between transfection with the TDP-43 gene and cell death. The insoluble fraction of TDP-43 indicates that TDP-43 has aggregated.

[0227] (Reference Example 2) Neuro2a cells were seeded onto a dish. One day after seeding, differentiation into neurons was initiated. Four days after seeding, the cells were transfected with the TDP-43 gene. Five hours after transfection, 10 nmol / L, 50 nmol / L, 100 nmol / L, 500 nmol / L, 1000 nmol / L, 5000 nmol / L, or 10,000 nmol / L of D-cycloserine or L-cycloserine was added to the medium. As a control, 10 nmol / L, 50 nmol / L, 100 nmol / L, 500 nmol / L, 1000 nmol / L, 5000 nmol / L, or 10,000 nmol / L of ropinirole was added to the medium. Ropinirole has been reported to have a therapeutic effect on ALS.

[0228] The percentage of dead cells was assessed 7 days after transfection of the TDP-43 gene. As shown in Figure 3A, cell death was not observed in cells that were not transfected with the TDP-43 gene. As shown in Figure 3B, cell death was observed in cells that were transfected with the TDP-43 gene but did not receive D-cycloserine, L-cycloserine, or ropinirole. As shown in Figure 3C, cell death was suppressed in cells that were transfected with the TDP-43 gene and received D-cycloserine.

[0229] As shown in Figure 4, D-cycloserine and L-cycloserine exhibited a concentration-dependent effect of suppressing cell death. 50 The EC value of L-cycloserine was 128 nmol / L. 50 The EC value of ropinirole was 237 nmol / L. 50 The relative survival rate represents the ratio of the number of surviving cells that overexpressed TDP-43 to the number of surviving cells that did not overexpress TDP-43, which was set at 100%.

[0230] Reference Example 3 Neuro2a cells were seeded onto a dish. One day after seeding, differentiation into neurons was initiated. Four days after seeding, the cells were transfected with the TDP-43 gene. Six hours after transfection, 10 μmol / L of D-cycloserine, L-cycloserine, ropinirole, or DMSO was added to the cells, and the cells were cultured for 12 hours. The soluble and insoluble fractions of TDP-43 in the cells were then analyzed, and the results are shown in Figure 5. As shown in Figure 5, in cells treated with DMSO as a control, the insoluble fraction of TDP-43 was confirmed to be greater than the soluble fraction. In contrast, in cells treated with D-cycloserine and L-cycloserine, the soluble fraction of TDP-43 was confirmed to be greater than the insoluble fraction of TDP-43.

[0231] The ratio of the insoluble fraction to the total of the soluble and insoluble fractions of intracellular TDP-43 was quantified and the results are shown in Figure 6. In cells treated with D-cycloserine and L-cycloserine, the ratio of the insoluble fraction was less than half.

[0232] Reference Example 4: 100 μL of EHS gel basement membrane matrix (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to 12.5 mL of DMEM (Dulbecco's Modified Eagle Medium, Fujifilm Wako Pure Chemical Industries, Ltd.) and mixed, and the mixture was added to a 24-well plate at 600 μL / well. The plate was left at room temperature for 2 hours, after which the solution was removed from the wells. Next, 600 μL of DMEM was added to each well, and the plate was left at room temperature for 2 hours.

[0233] Motor neurons derived from iPS cells from healthy individuals and from ALS patients were obtained from iXCells Biotechnologies. The motor neurons were quickly thawed in a 37°C incubator and suspended in motor neuron maintenance medium (iXCells Biotechnologies). The medium was centrifuged at 600×g for 5 minutes to collect the motor neurons, after which the medium was removed and the motor neurons were suspended in motor neuron maintenance medium.

[0234] The density of motor neurons is 3x10 5 After diluting the medium to 100 cells / mL, 600 μL of the medium containing motor neurons was placed in each of multiple wells of the matrix-coated plate and incubated at 37°C, 5% CO 2 Every 2-3 days, 300 μL of medium was removed from each of the multiple wells and 300 μL of fresh medium was added to each of the multiple wells.

[0235] On the seventh day after the start of culture, 300 μL of medium was removed from each of the wells, and 300 μL of medium containing 0.2% DMSO, 20 μmol / L D-cycloserine (Cayman Chemical), or 20 μmol / L ropinirole (Fujifilm Wako Pure Chemical Industries) was added to each of the wells. Every 2–3 days, 300 μL of medium was removed from each of the wells, and 300 μL of medium containing the same compound as the removed medium, i.e., 0.1% DMSO, 10 μmol / L D-cycloserine, or 10 μmol / L ropinirole, was added to each of the wells.

[0236] Cell extracts were prepared by adding 5 μL of a protease inhibitor and phosphatase inhibitor cocktail (Halt Protease and Phosphatase Inhibitor Cocktail, 10OX, registered trademark, Thermo Fisher Scientific) to 500 μL of detergent-containing protein extraction buffer (RIPA buffer, Nacalai Tesque). 50 μL of cell extract was added to motor neurons cultured for 20 days in the presence of DMSO, D-cycloserine, or ropinirole, and the cell extract was collected in a 1.5 mL tube by pipetting. The cell extract was centrifuged at 21,000 × g for 30 minutes at 4°C.

[0237] After centrifugation, 45 μL of the supernatant was collected, and 45 μL of electrophoresis buffer (AE-1430 EzApply, Atto) was added to the supernatant and heated at 95°C for 5 minutes to prepare a soluble protein fraction. After centrifugation, the precipitate was washed twice with 50 μL of RIPA buffer, and then 45 μL of RIPA buffer and 45 μL of electrophoresis buffer were added to the precipitate and heated at 95°C for 5 minutes to prepare an insoluble protein fraction.

[0238] SDS-PAGE of the soluble and insoluble protein fractions was performed, and the proteins were transferred to a PVDF membrane. The PVDF membrane was blocked by immersing it in blocking solution and shaking at room temperature for 1 hour. The PVDF membrane was then immersed in a solution containing TDP-43 polyclonal antibody (PGI Proteintech Group) and shaken overnight at 4°C. After washing the PVDF membrane three times with buffer, it was immersed in a solution containing HRP (horseradish peroxidase)-conjugated secondary antibody (Anti-Rabbit IgG, HRP-Linked F(ab')2 Fragment Donkey, Cytiva) and shaken at room temperature for 1 hour. After washing the PVDF membrane three times with buffer, the labeled secondary antibody was sensitized using 1 mL of luminescence reagent (Immunostar LD, Fujifilm Wako Pure Chemical Industries), and the PVDF membrane was photographed. The photograph of the PVDF membrane is shown in FIG.

[0239] As shown in Figure 7, in motor neurons derived from iPS cells from healthy subjects cultured in the presence of DMSO as a control, a band for the soluble fraction of TDP-43 was clearly observed, while a faint band for the insoluble fraction. In motor neurons derived from iPS cells from healthy subjects cultured in the presence of D-cycloserine, a band for the soluble fraction of TDP-43 was clearly observed, while a faint band for the insoluble fraction. In motor neurons derived from iPS cells from healthy subjects cultured in the presence of ropinirole, a band for the soluble fraction of TDP-43 was clearly observed, while a faint band for the insoluble fraction.

[0240] As shown in Figure 7, in motor neurons derived from iPS cells from an ALS patient cultured in the presence of DMSO as a control, a band for the soluble fraction of TDP-43 was clearly observed, and a band for the insoluble fraction was also clearly confirmed. In motor neurons derived from iPS cells from an ALS patient cultured in the presence of D-cycloserine, a band for the soluble fraction of TDP-43 was clearly observed, and a faint band for the insoluble fraction. In motor neurons derived from iPS cells from an ALS patient cultured in the presence of ropinirole, a band for the soluble fraction of TDP-43 was clearly observed, and a faint band for the insoluble fraction.

[0241] The captured image of the PVDF membrane was opened in ImageJ software and inverted using the Invert command. After removing the background using the Subtract Background command, the TDP-43 bands in each lane were successively enclosed in square frames of the same size, and the band intensities were quantified using the Measure command. The proportion of the insoluble fraction of TDP-43 was calculated from the band intensities of the soluble fraction of TDP-43 and the insoluble fraction of TDP-43 for each sample according to the following formula: R = {I I / (I I +I S )} × 100 In the above formula, R is the percentage of the insoluble fraction of TDP-43 (%), I I is the band intensity of the insoluble fraction of TDP-43, I S represents the band intensity of the soluble fraction of TDP-43.

[0242] Three experiments were performed, and the average value of the percentage of the insoluble fraction of TDP-43 was calculated. In Figure 8, the percentage of the insoluble fraction of TDP-43 in each experiment is indicated by dots, and the average value is indicated by bars. In motor neurons derived from iPS cells from healthy subjects, the average percentage of the insoluble fraction of TDP-43 was approximately 7.4%. On the other hand, in motor neurons derived from iPS cells from ALS patients, the average percentage of the insoluble fraction of TDP-43 was approximately 46.1%. However, in motor neurons derived from iPS cells from ALS patients in the presence of D-cycloserine, the average percentage of the insoluble fraction of TDP-43 decreased to approximately 17.4%. Furthermore, in motor neurons derived from iPS cells from ALS patients in the presence of ropinirole, the average percentage of the insoluble fraction of TDP-43 decreased to approximately 19.3%.

[0243] FTLD-TDP and ALS have many things in common, including the accumulation of TDP-43. Therefore, the decrease in the average percentage of the insoluble fraction of TDP-43 in motor neurons derived from iPS cells from ALS patients in the presence of D-cycloserine indicates that administration of D-cycloserine can also suppress TDP-43 accumulation in cells from FTLD-TDP patients.

[0244] Example 1 Neuro2a cells were seeded onto a dish. One day after seeding, differentiation into neurons was initiated. Four days after seeding, the cells were transfected with the TDP-43 gene. Five hours after transfection, 10 nmol / L, 30 nmol / L, 100 nmol / L, 300 nmol / L, 1000 nmol / L, 3000 nmol / L, or 10,000 nmol / L of D-cycloserine was added to the medium. Immediately thereafter, 10 nmol / L, 30 nmol / L, 100 nmol / L, 300 nmol / L, 1000 nmol / L, 3000 nmol / L, or 10,000 nmol / L of edaravone was further added to the medium containing D-cycloserine at each concentration.

[0245] The rate of dead cells was evaluated on day 7 after the cells were transfected with the TDP-43 gene. Figure 9 shows the relative cell viability for each concentration of D-cycloserine and edaravone. The relative viability refers to the percentage of surviving cells that overexpress TDP-43, when the number of surviving cells that do not overexpress TDP-43 is taken as 100%. The EC of the cell death inhibitory effect of D-cycloserine for each concentration of edaravone calculated from the results in Figure 9 was also calculated. 50 The EC20 values ​​of the cell death inhibitory effect of D-cycloserine were shown in Figures 10 and 11. 50 was 151.36 nmol / L when edaravone was 0 nmol / L, 149.44 nmol / L when edaravone was 10 nmol / L, 135.18 nmol / L when edaravone was 30 nmol / L, 118.85 nmol / L when edaravone was 100 nmol / L, 106.76 nmol / L when edaravone was 300 nmol / L, and 87.62 nmol / L when edaravone was 1000 nmol / L.

[0246] The synergistic effect of the combined use of D-cycloserine and edaravone was quantified using the combination index (CI) by Chou et al. (See TC Chou, P Talalay, Adv Enzyme Regul. 1984;22:27-55.) The CI was calculated using the following formula: In the above formula, Da represents the concentration of D-cycloserine that produces a 50% cell death inhibitory effect when D-cycloserine and edaravone are used in combination, Db represents the concentration of edaravone that produces a 50% cell death inhibitory effect when D-cycloserine and edaravone are used in combination, Dxa represents the concentration of D-cycloserine that produces a 50% cell death inhibitory effect when used alone, and Dxb represents the concentration of edaravone that produces a 50% cell death inhibitory effect when used alone.

[0247] A CI of 1 indicates an additive effect, a CI of > 1 indicates an antagonistic effect, and a CI of < 1 indicates a synergistic effect. As shown in Figure 11, the CI when D-cycloserine and edaravone were used in combination was 0.99 when edaravone was 10 nmol / L, 0.91 when edaravone was 30 nmol / L, 0.83 when edaravone was 100 nmol / L, and 0.83 when edaravone was 300 nmol / L. This indicates that the combined use of D-cycloserine and edaravone resulted in a synergistic effect.

Claims

1. An inhibitor of TDP-43 aggregation, comprising a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

2. The TDP-43 aggregation inhibitor according to claim 1, which comprises cycloserine or a salt thereof.

3. The TDP-43 aggregation inhibitor according to claim 1, wherein the cycloserine is D-cycloserine.

4. The TDP-43 aggregation inhibitor according to claim 1, wherein the cycloserine is L-cycloserine.

5. An inhibitor of TDP-43 aggregation, comprising at least one selected from the group consisting of cycloserine and terizidone, and salts thereof, in combination with edaravone.

6. The TDP-43 aggregation inhibitor according to claim 5, which comprises cycloserine or a salt thereof.

7. The TDP-43 aggregation inhibitor according to claim 5, wherein the cycloserine is D-cycloserine.

8. The TDP-43 aggregation inhibitor according to claim 5, wherein the cycloserine is L-cycloserine.

9. The TDP-43 aggregation inhibitor according to claim 1, comprising at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

10. The TDP-43 aggregation inhibitor according to claim 1, comprising 30 mg or more and 60 mg or less of edaravone.

11. The TDP-43 aggregation inhibitor according to claim 1, which does not contain acamprosate.

12. An inhibitor of TDP-43 aggregation, comprising edaravone in combination with at least one selected from the group consisting of cycloserine and terizidone, and salts thereof.

13. The TDP-43 aggregation inhibitor according to claim 12, comprising cycloserine or a salt thereof.

14. The TDP-43 aggregation inhibitor according to claim 12, wherein the cycloserine is D-cycloserine.

15. The TDP-43 aggregation inhibitor according to claim 12, wherein the cycloserine is L-cycloserine.

16. The TDP-43 aggregation inhibitor according to claim 12, which is used in combination with at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

17. The TDP-43 aggregation inhibitor according to claim 12, comprising 30 mg or more and 60 mg or less of edaravone.

18. The TDP-43 aggregation inhibitor according to claim 12, which does not contain acamprosate.

19. An agent for suppressing cell death in cells in which TDP-43 is overexpressed, comprising a combination of edaravone and at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

20. An inhibitor of cell death in a cell in which TDP-43 is overexpressed according to claim 19, comprising cycloserine or a salt thereof.

21. The inhibitor of cell death in a cell in which TDP-43 is overexpressed according to claim 19, wherein the cycloserine is D-cycloserine.

22. The inhibitor of cell death in a cell in which TDP-43 is overexpressed according to claim 19, wherein the cycloserine is L-cycloserine.

23. The inhibitor of cell death of cells in which TDP-43 is overexpressed according to claim 19, comprising at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

24. The inhibitor of cell death of cells in which TDP-43 is overexpressed according to claim 19, comprising 30 mg or more and 60 mg or less of edaravone.

25. The inhibitor of cell death of a cell in which TDP-43 is overexpressed according to claim 19, which does not contain acamprosate.

26. An inhibitor of cell death in cells in which TDP-43 is overexpressed, comprising at least one selected from the group consisting of cycloserine and terizidone, and salts thereof, used in combination with edaravone.

27. An inhibitor of cell death in a cell in which TDP-43 is overexpressed according to claim 26, comprising cycloserine or a salt thereof.

28. The inhibitor of cell death in a cell in which TDP-43 is overexpressed according to claim 26, wherein the cycloserine is D-cycloserine.

29. The inhibitor of cell death in a cell in which TDP-43 is overexpressed according to claim 26, wherein the cycloserine is L-cycloserine.

30. The inhibitor of cell death of cells in which TDP-43 is overexpressed according to claim 26, comprising at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

31. The inhibitor of cell death in cells in which TDP-43 is overexpressed according to claim 26, used in combination with 30 mg or more and 60 mg or less of edaravone.

32. The inhibitor of cell death of a cell in which TDP-43 is overexpressed according to claim 26, which does not contain acamprosate.

33. An inhibitor of cell death in cells in which TDP-43 is overexpressed, comprising edaravone in combination with at least one selected from the group consisting of cycloserine and terizidone, and salts thereof.

34. An inhibitor of cell death in a cell in which TDP-43 is overexpressed according to claim 33, comprising cycloserine or a salt thereof.

35. The inhibitor of cell death in a cell in which TDP-43 is overexpressed according to claim 33, wherein the cycloserine is D-cycloserine.

36. The inhibitor of cell death in a cell in which TDP-43 is overexpressed according to claim 33, wherein the cycloserine is L-cycloserine.

37. The inhibitor of cell death of cells in which TDP-43 is overexpressed according to claim 33, which is used in combination with at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

38. The inhibitor of cell death of cells in which TDP-43 is overexpressed according to claim 33, comprising 30 mg or more and 60 mg or less of edaravone.

39. An inhibitor of cell death in a cell in which TDP-43 is overexpressed according to claim 33, which does not contain acamprosate.

40. A therapeutic or preventive agent for a disease associated with TDP-43 aggregation, comprising a combination of at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, and edaravone.

41. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 40, comprising cycloserine or a salt thereof.

42. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 40, wherein the cycloserine is D-cycloserine.

43. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 40, wherein the cycloserine is L-cycloserine.

44. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 40, wherein the disease accompanied by TDP-43 aggregation is TDP-43 proteinopathy.

45. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 44, wherein the TDP-43 proteinopathy is at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular dystrophy.

46. ​​The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 44, wherein the TDP-43 proteinopathy is amyotrophic lateral sclerosis.

47. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 40, comprising at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

48. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 40, comprising 30 mg or more and 60 mg or less of edaravone.

49. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 40, which does not contain acamprosate.

50. An agent for treating or preventing a disease accompanied by aggregation of TDP-43, comprising at least one selected from the group consisting of cycloserine, terizidone, and salts thereof, in combination with edaravone.

51. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 50, comprising cycloserine or a salt thereof.

52. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 50, wherein the cycloserine is D-cycloserine.

53. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 50, wherein the cycloserine is L-cycloserine.

54. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 50, wherein the disease accompanied by TDP-43 aggregation is TDP-43 proteinopathy.

55. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 54, wherein the TDP-43 proteinopathy is at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular dystrophy.

56. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 54, wherein the TDP-43 proteinopathy is amyotrophic lateral sclerosis.

57. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 50, comprising at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

58. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 50, used in combination with 30 mg or more and 60 mg or less of edaravone.

59. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 50, which does not contain acamprosate.

60. A therapeutic or preventive agent for a disease accompanied by aggregation of TDP-43, comprising edaravone in combination with at least one selected from the group consisting of cycloserine, terizidone, and salts thereof.

61. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 60, comprising cycloserine or a salt thereof.

62. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 60, wherein the cycloserine is D-cycloserine.

63. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 60, wherein the cycloserine is L-cycloserine.

64. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 60, wherein the disease associated with TDP-43 aggregation is TDP-43 proteinopathy.

65. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation described in claim 64, wherein the TDP-43 proteinopathy is at least one selected from the group consisting of amyotrophic lateral sclerosis, frontotemporal lobar degeneration, primary lateral sclerosis, and progressive muscular dystrophy.

66. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 64, wherein the TDP-43 proteinopathy is amyotrophic lateral sclerosis.

67. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 60, used in combination with at least one selected from the group consisting of 15 mg or more and less than 250 mg of cycloserine, terizidone, and salts thereof.

68. The therapeutic or preventive agent for a disease accompanied by TDP-43 aggregation according to claim 60, comprising 30 mg or more and 60 mg or less of edaravone.

69. The therapeutic or preventive agent for a disease associated with TDP-43 aggregation according to claim 60, which does not contain acamprosate.