JPWO2018235728A1 - 神経障害を改善するための医薬組成物 - Google Patents
神経障害を改善するための医薬組成物 Download PDFInfo
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- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- YUMLNTJCWGYGQU-UHFFFAOYSA-N zinc azane Chemical compound N.N.[Zn+2] YUMLNTJCWGYGQU-UHFFFAOYSA-N 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- FUTVBRXUIKZACV-UHFFFAOYSA-J zinc;3-[18-(2-carboxylatoethyl)-8,13-bis(ethenyl)-3,7,12,17-tetramethylporphyrin-21,24-diid-2-yl]propanoate Chemical compound [Zn+2].[N-]1C2=C(C)C(CCC([O-])=O)=C1C=C([N-]1)C(CCC([O-])=O)=C(C)C1=CC(C(C)=C1C=C)=NC1=CC(C(C)=C1C=C)=NC1=C2 FUTVBRXUIKZACV-UHFFFAOYSA-J 0.000 description 1
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Abstract
Description
[1] 染色体上の3塩基繰り返し配列(トリプレットリピート)の存在に起因する神経障害を有する対象の予防または治療において使用するための医薬組成物であって、
下記式(I):
で示される化合物またはその塩もしくはエステルを含有する、
ことを特徴とする
医薬組成物。
前記対象は、フリードライヒ失調症(FRDA)、球脊髄性筋委縮症、ハンチントン病(HD)、脊髄小脳変性症1型(SCA1)、脆弱X随伴振戦/運動失調症候群(FXTAS)、脆弱X症候群(FRAXA)、筋緊張性ジストロフィーからなる群から選択されるトリプレットリピート病を患う対象である、
ことを特徴とする
医薬組成物。
前記対象は、脆弱X随伴振戦/運動失調症候群(FXTAS)または脆弱X症候群(FRAXA)を患う対象である、
ことを特徴とする
医薬組成物。
R1が、水素原子、炭素数1〜8のアルカノイル基、および、炭素数7〜14のアロイル基からなる群から選択され、
R2が、水素原子、直鎖または分岐状の炭素数1〜8のアルキル基、炭素数3〜8のシクロアルキル基、炭素数6〜14のアリール基、および、炭素数7〜15のアラルキル基からなる群から選択される
ことを特徴とする、
医薬組成物。
R1およびR2が、水素原子である、
医薬組成物。
一種または二種以上の金属含有化合物をさらに含有する、
医薬組成物。
金属含有化合物が、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、銅、クロム、モリブデンまたはコバルトを含有する化合物である、
医薬組成物。
金属含有化合物が、鉄、マグネシウムまたは亜鉛を含有する化合物である、
医薬組成物。
金属含有化合物が、鉄を含有する化合物である、
医薬組成物。
前記鉄を含有する化合物が、クエン酸第一鉄ナトリウムである、
医薬組成物。
で示される化合物またはその塩もしくはエステルの使用。
それを必要とする対象に、治療上有効量の下記式(I):
で示される化合物またはその塩もしくはエステルを投与することを含む、
ことを特徴とする、
方法。
本発明は、染色体上の3塩基繰り返し配列(トリプレットリピート;TR)の存在に起因する神経障害を有する対象の予防または治療において使用するための医薬組成物に関する。
本明細書において、ALA類とは、ALA若しくはその誘導体またはそれらの塩またはエステルをいう。
マウス大脳皮質初代培養神経細胞に、CGG88回反復伸長発現プラスミドまたはコントロールとしてのGFP発現プラスミドを発現させた各神経細胞を作製した。
プラスミドの細胞へのトランスフェクションは、NEPA21エレクトロポレーター(ネッパジーン社)を用い、エレクトロポレーション法にて行った。
ヒト由来ゲノムからCGG88回反復配列を含むDNAを取得し、pCAG−neoベクター(Wako社)に挿入し、さらに、CGG88回反復配列の下流にpEGFP−C1 Vector(clontech社)由来のGFP遺伝子を挿入した。QIAGEN Plasmid Maxi Kit(キアゲン社)を用いて精製したプラスミドを、CGG88回反復伸長発現プラスミドとして用いた。また、CGG88回反復配列を挿入せずに、GFP遺伝子のみを挿入したプラスミドを、GFP発現プラスミドとして用いた。前記各細胞は21日間培養した。培地は、B−27(登録商標)サプリメント(2%)(インビトロジェン社)およびGlutaMaxTMサプリメント(1%)(インビトロジェン社)を添加したNeurobasalTM Medium(インビトロジェン社)(神経細胞用メディウム)を用いて、37℃、5%CO2存在下で培養した。1μM ALA+0.05μM SFC(ALAとSFCをモル比で20:1の割合で混合)を培養14日目から1週間培養液中に投与した。
培養21日後の各神経細胞に対して、ホールセルパッチクランプ法にて自発性の興奮性シナプス後電流(spontaneous excitatory postsynaptic currents(sEPSCs))を神経活動の指標として測定した。
ホールセルパッチクランプ法は、細胞膜に微小ガラス電極をギガオーム以上の高抵抗で密着させた後、さらに吸引することでガラス電極が密着している部分の細胞膜に穴をあけ、全細胞膜を流れるイオン電流を記録する方法である。本実施例においては、以下の装置、試薬、条件を用いた:
アンプ装置:EPC10 amplifier(HEKA,Lambrecht/Pfalz,Germany)
外液(in mM):143 NaCl,5 KCl,2 CaCl2,1 MgCl2,10glucose,10 HEPES,pH7.4 with NaOH;
内液(in mM):135 CsMeS,5 CsCl,10 HEPES,0.5 EGTA,1 MgCl2,4 Mg2ATP,0.4 NaGTP,5 QX−314,pH7.4 with CsOH.
膜電位:−70mVに固定し測定。
図1から分かるとおり、CGG88回反復伸長発現神経細胞において低下した神経活動(図1内「CGG repeat」)がALA+SFC処置により改善した(図1内「CGG repeat + 5−ALA」)。
<実施例2>マウス大脳皮質初代培養神経細胞におけるALAの神経活動改善効果の神経形態学的評価
<実施例1>で使用した各神経細胞について、培養21日後に、4%パラホルムアルデヒドで固定し、神経細胞マーカーとしての抗MAP2抗体(ab5392、アブカム社、1/1,000希釈)、および抗GFP抗体(ab290、アブカム社、1/1,000希釈)を用いて細胞染色を行った。固定した細胞をTriton X−100(0.1%)を含むPBSで10分間洗浄し、上記抗体(1次抗体)存在下、4℃でインキュベートした。その後、PBSで洗浄し、蛍光標識された2次抗体(DyLight 405‐AffiniPure Donkey Anti−Chicken IgY(Jackson ImmunoResearch社、1/500希釈)およびAlexa Fluor 488‐conjugated donkey anti−rabbit IgG(インビトロジェン社、1/500希釈))で染色した。染色後、PBSで洗浄し、共焦点顕微鏡(LSM700、カールツァイス社)で撮影した。
図2から分かるとおり、CGG88回反復伸長発現神経細胞において低下した神経細胞突起分岐数(図2内「CGG repeat」)が、ALA+SFC処置により改善した(図2内「CGG repeat + ALA」)。
<実施例3>脆弱X随伴振戦/失調症候群(FXTAS)モデルマウスに対するALAの行動改善効果の評価
wild−typeマウスおよび上記のモデルマウスに対し、薬剤投与群(ALA塩酸塩とSFC併用投与)、Vehicle群(SFCのみを投与)をそれぞれ設定し、試験群として計4群を用いた。また、ALA塩酸塩の投与量は、1回投与あたり3mg/kgとして用いた。
薬剤投与群においては、ALAとSFCとがモル比で20:1の割合で含む水溶液を調製し、試験に用いた。具体的には、ALA塩酸塩3mg/kgに対して、SFC0.47mg/kgを使用した。
各群のマウスを細長い板の上(長さ80cm、幅5mm)で歩かせ、この細長い板上で足を滑らせる(スリップ)回数を数えた。
新規物体認識試験とは、記憶により旧知物体に対する探索行動が新規物体に対するものより低下するというマウスの習性を利用した学習・記憶能力試験である。
マウスの自発的交替行動を試験する当業者に周知の試験である。具体的に、探索行動で自発的にY字迷路の異なるアームに入るマウスの性質を利用した試験方法であり、マウスをY字迷路中で自由に行動させ、既に入ったアームについての記憶を評価することで、マウスの注意力、空間記憶を評価するものである。
測定では、8分間マウスが3本のarmに入る順序を記録する。すべてのarmに侵入した回数と続けて3回異なるarmに入った回数(最少回数3回ですべてのarmに侵入した回数:交替行動数)を数え、交替行動数をarmの総侵入回数引く2で割った値を交替行動率として評価する。
Claims (12)
- 染色体上の3塩基繰り返し配列(トリプレットリピート)の存在に起因する神経障害を有する対象の予防または治療において使用するための医薬組成物であって、
下記式(I):
で示される化合物またはその塩もしくはエステルを含有する、
ことを特徴とする
医薬組成物。 - 請求項1に記載の医薬組成物であって、
前記対象は、フリードライヒ失調症(FRDA)、球脊髄性筋委縮症、ハンチントン病(HD)、脊髄小脳変性症1型(SCA1)、脆弱X随伴振戦/運動失調症候群(FXTAS)、脆弱X症候群(FRAXA)、筋緊張性ジストロフィーからなる群から選択されるトリプレットリピート病を患う対象である、
ことを特徴とする
医薬組成物。 - 請求項1または2に記載の医薬組成物であって、
前記対象は、脆弱X随伴振戦/運動失調症候群(FXTAS)または脆弱X症候群(FRAXA)を患う対象である、
ことを特徴とする
医薬組成物。 - 請求項1〜3のいずれか1項に記載の医薬組成物であって、
R1が、水素原子、炭素数1〜8のアルカノイル基、および、炭素数7〜14のアロイル基からなる群から選択され、
R2が、水素原子、直鎖または分岐状の炭素数1〜8のアルキル基、炭素数3〜8のシクロアルキル基、炭素数6〜14のアリール基、および、炭素数7〜15のアラルキル基からなる群から選択される
ことを特徴とする、
医薬組成物。 - 請求項1〜4のいずれか1項に記載の医薬組成物であって、
R1およびR2が、水素原子である、
医薬組成物。 - 請求項1〜5のいずれか1項に記載の医薬組成物であって、
一種または二種以上の金属含有化合物をさらに含有する、
医薬組成物。 - 請求項6に記載の医薬組成物であって、
金属含有化合物が、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、銅、クロム、モリブデンまたはコバルトを含有する化合物である、
医薬組成物。 - 請求項7に記載の医薬組成物であって、
金属含有化合物が、鉄、マグネシウムまたは亜鉛を含有する化合物である、
医薬組成物。 - 請求項8に記載の医薬組成物であって、
金属含有化合物が、鉄を含有する化合物である、
医薬組成物。 - 請求項9に記載の医薬組成物であって、
前記鉄を含有する化合物が、クエン酸第一鉄ナトリウムである、
医薬組成物。 - 染色体上の3塩基繰り返し配列(トリプレットリピート)の存在に起因する神経障害を有する対象を予防または治療するための医薬の製造における下記式(I):
で示される化合物またはその塩もしくはエステルの使用。 - 染色体上の3塩基繰り返し配列(トリプレットリピート)の存在に起因する神経障害を有する対象を予防または治療する方法であって、
それを必要とする対象に、治療上有効量の下記式(I):
で示される化合物またはその塩もしくはエステルを投与することを含む、
ことを特徴とする、
方法。
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