JP7170875B2 - アミロイド性脳神経疾患の治療用組成物および治療方法 - Google Patents
アミロイド性脳神経疾患の治療用組成物および治療方法 Download PDFInfo
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Description
(1)アミロイド-ベータの凝集レベルが正常よりも高いか、または高い危険性がある対象(患者)、
(2)タウタンパク質の凝集レベルが正常よりも高いか、または高い危険性がある対象(患者)、
(3)タウタンパク質のリン酸化レベルが正常よりも高いか、または高い危険性がある対象(患者)、
(4)上記の(1)~(3)中の1つ以上に該当する対象(患者)からなる群より選択される対象(患者)に適用するためのものであってもよい。
1.1. 試料の用意
リファペンチンを5mMの濃度になるようにDMSOに溶解した。 その後、上記の化合物を、6%のDMSO(in DW)を利用して希釈し、使用した。
先に用意したアミロイド-ベータ溶液を、1.5mLのマイクロ遠心分離管に、50μMになるようにそれぞれ入れ、1.5mLのマイクロ遠心分離管毎にリファペンチンとトリフルプロマジンとを2μMの濃度で処理した後、37℃で72時間反応させた。
2.1. 試料の用意
リファペンチンを5mMの濃度になるようにDMSOに溶解した。 その後、上記の化合物を、6%のDMSO(in DW)を利用して希釈し、使用した。
上記の実施例2.1で用意したアミロイド-ベータの溶液を、1.5mLのマイクロ遠心分離管に、25μMになるようにそれぞれ入れた後、37℃で72時間反応させた。
上記の実施例2.1で用意した試料からのアミロイド-ベータの凝集分解を確認するために、次のようにSDS-PAGE分析を行った。
3.1. 試料の用意
化合物(リファペンチン、リファンピシン、リファブチン、リファマイシンSV、リファマイシンB、リファマイシンS、リファキシミン、リファンジン、以上にリファマイシン系誘導体)は、5mMの濃度になるようにDMSOに溶解した。 その後、上記の化合物を、6%のDMSO(in DW)を利用して希釈し、使用した。
上記の実施例3.1で用意したアミロイド-ベータの溶液を、1.5mLのマイクロ遠心分離管に、50μMになるようにそれぞれ投入した後、37℃で72時間反応させた。
4.1. APP/PS1 TGマウスモデルの用意
遺伝子組み換えのマウス(APP/PS1 TG;アルツハイマー疾患が発症した動物モデル;B6C3-Tg(APPswe、PSEN1dE)85Dbo/Mmjax)および野生型マウス(WT)は、Jackson Laboratory(Bar Harbor、Maine、USA)から入手した。 APP/PS1 TGマウスは、野生型マウスと交差して二重半接合体(double hemizygotes)に維持された。 すべての遺伝子型は、Jackson Laboratoryの標準PCR条件に応じて、尾のDNA(tail DNA)を用いたPCR分析によって確認された。 マウスは、動物飼育室でプラスチックケージ当たり1匹ずつ収容され、12時間の明暗サイクルが交互に21±1℃で維持され、餌と水を自由に摂取した。
10ヵ月齢のAPP/PS1 TGマウスに、リファペンチンを9週間200mg/kgの濃度で週1回(TG、RP 200 QW)または50mg/kgの濃度で2日に一回(TG、RP 50 QOD)経口投与した。 対照群に同量の媒体(vehicle;Veh)(DW中の0.5%MC)を投与した。 上記の投与は、経口投与用ゾンデを使用し、マウスの体重に基づいて10ml/kg(v/w)の媒体に溶解して投与した。
2%のアベルティン(20mg/g、i.p.)でマウスに麻酔をかけた。 上記のマウスに0.9%NaClで灌流を行い、脳を切除した。 上記のヘミブレインは、4℃で4%のパラホルムアルデヒド(pH7.4)を用いて一晩固定した。 パラホルムアルデヒドによって固定された脳は、脱水化の過程を経て、パラフィンを使用し、組織ブロックを作製した。
上記の実施例4.3で用意したパラフィンによって固定された脳組織を5~6μmの厚さの切片に作製し、免疫組織の化学染色を行った。 組織切片は、脱ワックス、再水和物、および1%過酸化水素を利用し、内因性パーオキシダーゼを除去した後、非特異的反応を抑制するために、ヤギの10%(v/v)正常血清を用いて60分間ブロッキング過程を経た後、Aβ抗体を利用し、プラークを染色(一晩、4℃)した。 翌日、PBSで洗浄した後、ABC kit(Vectastin ABC kit、Vector Laboratories)を用いて、2次抗体を染色した後、顕微鏡で観察した。 図8のアミロイド-ベータプラークの染色画像と、図9および図10のグラフとに示されたように、対照群のマウス(TG-Veh)と比較したとき、リファペンチンを投与したマウスにおいて、上記のプラーク数および総プラークの面積が減少した。
5.1. 5X FADマウスモデルの用意
遺伝子組み換えのマウス(5X FAD;アルツハイマー疾患が発症した動物モデル;B6SJL-Tg(APPSwFlLon、PSEN1 * M146L * L286V)6799Vas/Mmjax))および野生型マウスをJackson Laboratory(Bar Harbor、Maine、USA)から入手した。 5X FADマウスは、野生型マウスと交差して二重半接合体(double hemizygotes)に維持した。 すべての遺伝子型は、Jackson Laboratoryの標準PCR条件に応じて、尾のDNA(tail DNA)を用いたPCR分析によって確認した。 マウスは、動物飼育室でプラスチックケージ当たり4~6匹ずつ収容され、12時間の明暗サイクルが交互に21±1℃の条件で維持され、餌と水を自由に摂取した。
7ヵ月齢の5X FADマウスに、トリフルプロマジンを50 mg/kgの濃度で3週間二日に一回経口投与した。 対照群には、同量のビークル(vehicle)(PBS中の1%(w/v)DMSO)を投与した。 上記の投与は、経口投与用ゾンデを使用し、マウスの体重に基づいて10 ml/kg(v/w)のビークルに溶解して投与した。
2%(w/v)のアベルティン(20mg/g、i.p.)でマウスに麻酔をかけた。 上記のマウスに0.9%(w/v)NaClで灌流を行い、脳を切除した。 上記のヘミブレインは、4℃で4%(w/v)のパラホルムアルデヒド(pH7.4)を用いて一晩固定した。 凍結保存のために、脳を30%(w/v)のスクロースに48時間の間に浸した。 上記の他のヘミブレインを皮質と海馬領域とで解剖し、1xプロテアーゼ阻害剤カクテルを含む溶解緩衝液(10mMのTris-HCl、320mMのスクロース内の5mMのEDTA、pH7.4)の中で30分間に氷上で均質化した。 上記のサンプルは、4℃、13500rpmで30分間遠心分離した。 BCAタンパク質分析キット(thermoFisher、cat#232250)を用いて、メーカの指示に従って溶解物の濃度を測定した。 上記の吸光度は、560nmで読み取った。
冷凍した脳をチオフラビンS(thioflavin S(ThS))を利用して染色するためには、低温維持装置(Leica CM1800)を使用し、35umの厚さに脳を切って組織切片を作製した後、Aβプラークを染色した。 ThS染色は、エタノール(50%(v/v))を用いて500uMの濃度で7分間行った。 その後、上記の切片を100%、90%、および70%(v/v)のエタノールで順に10秒間洗い、PBSに入れた。 Leica DM2500蛍光顕微鏡を使用して画像を得た。 図11に示すように、対照群のマウス(ビークル、1%(w/v)DMSO in PBS)と、本発明のトリフルプロマジンが投与されたマウスとを比較すると、トリフルプロマジンが投与されたマウスでプラーク数および総プラーク面積が減少した。
Aβプラークと共にアルツハイマー性認知症、パーキンソン疾患の主な原因となるタンパク質であるタウ(Tau)の変化をウエスタンブロット(Western blot)分析を用いて確認した。 上記の用意した組織のサンプルをSDS-PAGEで分離し、PVDF膜に移した。 上記の膜は、1次抗体を用いて、4℃で一晩処理した。 1次抗体としては、Total Tau(T-Tau)、リン酸化されたタウ(P-Tau)を検知することができる抗体を使用しており、Horseradish Peroxidase(HRP)が結合された(conjugated)2次抗体を用いて検出した。 上記のblot展開は、メーカの指示に従って、Clarity Western ECL substrate(Bio-Rad)で行った。
6.1. APP/PS1 TGマウスモデルの用意
遺伝子組み換えのマウス(APP/PS1 TG;アルツハイマー疾患が発症した動物モデル;B6C3-Tg(APPswe、PSEN1dE)85Dbo/Mmjax)および野生型マウスは、Jackson Laboratory(Bar Harbor、Maine、USA)から入手した。 このようなAPP/PS1 TGマウスは、野生型マウスと交差して二重半接合体(double hemizygotes)に維持された。 すべての遺伝子型は、Jackson Laboratoryの標準PCR条件に応じて、尾のDNA(tail DNA)を用いたPCR分析によって確認された。 マウスは、動物飼育室でプラスチックケージ当たり1匹ずつ収容され、12時間の明暗サイクルが交互に21±1℃で維持され、餌と水を自由に摂取した。
10ヵ月齢のAPP/PS1 TGマウスに、リファペンチンを9週間200 mg/kgの濃度で週1回または50 mg/kgの濃度で2日に一回経口投与した。 対照群に同量の媒体(vehicle)(DW中の0.5%MC)を投与した。 上記の投与は、経口投与用ゾンデを使用し、マウスの体重に基づいて10 ml/kg(v/w)の媒体に溶解して投与した。
Y字迷路の評価は、40cmの長さ(15cmの壁の高さ)を有する3つの同じアームを120度の角度で配置して作製した迷路枠を利用した。 この実験は、げっ歯類の本能的な探索習性を利用した行動実験であり、新たな領域を探索する可能性が高いことに着目した方法であった。 直前に探索されたアームを記憶し、同じアームに入らないほど高い記憶力の数値を示した。 個体毎に8分の探索時間を提供し、最終的な結果は、自発的交替行動変動率(%)の値で表した。 自発的交替行動変動率(%)は、次の数式で計算した。
[数式]
自発的交替行動変動率(%)=トリプレット数/(全体アーム進入-2)
新規物体認識試験は、40cm×40cmのアクリルケージに、異なる2つの物体を利用して記憶力を評価した。 アクリルケージ内に慣らされた後、2つの物体を一定の位置に置いて、自由に認知させた後、各物体を探索した時間を測定した。 24時間の遅延時間を個体毎に与え、再び同じ位置であるが1つの物体のみを他の物体に変更した。 このとき、変更した物体を新規物体として認識し、探索時間が長くなるほど、記憶力が良いと判断することができる。 24時間前の物体を記憶しないと、新規物体と既存物体とを区別できず、両方の物体を均一に探索する可能性がある。 合計10分間に自由に探索するようにさせ、その結果、選好指標値(新しい個体探索時間/合計探索時間)に示した。 分析は、SMART VIDEO TRACKING Software(Panlab、USA)を用いて実施した。 実験で得られたすべてのデータは、平均±標準誤差平均(SEM)で表記し、比較対象群である薬物適用群間の比較、および薬物非適用群との比較を行い、スチューデントのt検定で群間の分析を実施した。 図14に示すように、遺伝子組み換えのアルツハイマー性認知症が発症した動物(APP/PS1 TG)において、リファペンチンを投与した後、8週目に新規物体認知試験(Novel Object Recognition)を実施した結果、実験動物が新しい物体を探索する頻度を測定して得た選好指標値(Preference Index)が大きくなることから、陰性対照群(TG-Veh)に比べて陽性対照群(WT-Veh)に近く記憶力の数値が向上したことがわかる。
Claims (5)
- リファペンチン(rifapentine)又は薬学的に許容可能なその塩を有効成分として含む神経変性脳疾患(neurodegenerative brain disease)の予防または治療用薬学的組成物。
- 次の(1)~(4)から選択された対象に投与する、請求項1に記載の薬学的組成物。
(1)アミロイド-ベータの凝集レベルが神経変性疾患を有しない正常よりも高い患者、
(2)タウタンパク質の凝集レベルが神経変性疾患を有しない正常よりも高い患者、
(3)タウタンパク質のリン酸化レベルが神経変性疾患を有しない正常よりも高い患者、
(4)前記(1)~(3)中の1つ以上に該当する患者。 - 前記神経変性脳疾患は、アルツハイマー疾患(Alzheimer’s disease)、パーキンソン疾患、ハンチントン疾患、軽度認知障害(mild cognitive impairment)、大脳アミロイド血管症、ダウン症候群、アミロイド性脳卒中(stroke)、全身性アミロイドーシス、ダッチ(Dutch)型アミロイドーシス、ニーマン・ピック疾患、老人性認知症、筋萎縮性側索硬化症(amyotrophic lateral sclerosis)、脊髄小脳運動失調症(Spinocerebellar Atrophy)、ツーレット症候群(Tourette`s Syndrome)、フリードライヒ運動失調症(Friedrich` s Ataxia)、マチャド・ジョセフ病(Machado-Joseph`s disease)、レビー小体型認知症(Lewy Body Dementia)、ジストニア(Dystonia)、進行性核上性麻痺(Progressive Supranuclear Palsy)、および前頭側頭型認知症(Frontotemporal Dementia)からなる群より選択される、請求項1に記載の薬学的組成物。
- リファペンチン(rifapentine)又は食品学的に許容可能なその塩を有効成分として含む神経変性脳疾患(neurodegenerative brain disease)の予防または改善用健康機能性食品。
- リファペンチン(rifapentine)又は食品学的に許容可能なその塩を有効成分として含む、認知障害の予防または記憶力改善用健康機能性食品。
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2020
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Non-Patent Citations (2)
Title |
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BRAIN,2016年,Vol.139,pp.1568-1586 |
Dement. Geriatr. Cogn. Disord. Extra.,2017年,Vol.7,pp.204-214 |
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EP3888655B1 (en) | 2023-08-30 |
WO2020111824A1 (ko) | 2020-06-04 |
EP3888655C0 (en) | 2023-08-30 |
KR102651174B1 (ko) | 2024-03-26 |
KR102081785B1 (ko) | 2020-02-27 |
EP3888655A4 (en) | 2022-03-16 |
EP3888655A1 (en) | 2021-10-06 |
CN113164471A (zh) | 2021-07-23 |
JP2022515019A (ja) | 2022-02-17 |
KR20200066268A (ko) | 2020-06-09 |
US20200330474A1 (en) | 2020-10-22 |
KR102051624B1 (ko) | 2019-12-02 |
ES2962814T3 (es) | 2024-03-21 |
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