JP2016533346A - コレステロール誘発性ミトコンドリア機能不全を治療するための芳香族カチオン性ペプチドの使用 - Google Patents
コレステロール誘発性ミトコンドリア機能不全を治療するための芳香族カチオン性ペプチドの使用 Download PDFInfo
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Abstract
Description
本出願は、2013年9月27日出願の米国出願第61/883,513号の利益及び優先権を主張し、その全体が参照により本明細書に組み込まれる。
芳香族カチオン性ペプチド
1.少なくとも1個の正味の正電荷、
2.最低で3個のアミノ酸、
3.最大で約20個のアミノ酸、
4.3pmがr+1以下の最大数である、正味の正電荷の最小数(pm)とアミノ酸残基の総数(r)との関係、及び
5.aが1である場合にptも1であり得ることを除いて、2aがpt+1以下の最大数である、芳香族基の最小数(a)と正味の正電荷の総数(pt)との関係を含む。
D−Arg−Dmt−Lys−Trp−NH2、
D−Arg−Trp−Lys−Trp−NH2、
D−Arg−2′,6′−Dmt−Lys−Phe−Met−NH2、
H−D−Arg−Dmt−Lys(NαMe)−Phe−NH2、
H−D−Arg−Dmt−Lys−Phe(NMe)−NH2、
H−D−Arg−Dmt−Lys(NαMe)−Phe(NMe)−NH2、
H−D−Arg(NαMe)−Dmt(NMe)−Lys(NαMe)−Phe(NMe)−NH2、
D−Arg−Dmt−Lys−Phe−Lys−Trp−NH2、
D−Arg−Dmt−Lys−Dmt−Lys−Trp−NH2、
D−Arg−Dmt−Lys−Phe−Lys−Met−NH2、
D−Arg−Dmt−Lys−Dmt−Lys−Met−NH2、
H−D−Arg−Dmt−Lys−Phe−Sar−Gly−Cys−NH2、
H−D−Arg−Ψ[CH2−NH]Dmt−Lys−Phe−NH2、
H−D−Arg−Dmt−Ψ[CH2−NH]Lys−Phe−NH2、
H−D−Arg−Dmt−LysΨ[CH2−NH]Phe−NH2、
H−D−Arg−Dmt−Ψ[CH2−NH]Lys−Ψ[CH2−NH]Phe−NH2、
Lys−D−Arg−Tyr−NH2、
Tyr−D−Arg−Phe−Lys−NH2、
2′,6′−Dmt−D−Arg−Phe−Lys−NH2、
Phe−D−Arg−Phe−Lys−NH2、
Phe−D−Arg−Dmt−Lys−NH2、
D−Arg−2′6′Dmt−Lys−Phe−NH2、
H−Phe−D−Arg−Phe−Lys−Cys−NH2、
Lys−D−Arg−Tyr−NH2、
D−Tyr−Trp−Lys−NH2、
Trp−D−Lys−Tyr−Arg−NH2、
Tyr−His−D−Gly−Met、
Tyr−D−Arg−Phe−Lys−Glu−NH2、
Met−Tyr−D−Lys−Phe−Arg、
D−His−Glu−Lys−Tyr−D−Phe−Arg、
Lys−D−Gln−Tyr−Arg−D−Phe−Trp−NH2、
Phe−D−Arg−Lys−Trp−Tyr−D−Arg−His、
Gly−D−Phe−Lys−Tyr−His−D−Arg−Tyr−NH2、
Val−D−Lys−His−Tyr−D−Phe−Ser−Tyr−Arg−NH2、
Trp−Lys−Phe−D−Asp−Arg−Tyr−D−His−Lys、
Lys−Trp−D−Tyr−Arg−Asn−Phe−Tyr−D−His−NH2、
Thr−Gly−Tyr−Arg−D−His−Phe−Trp−D−His−Lys、
Asp−D−Trp−Lys−Tyr−D−His−Phe−Arg−D−Gly−Lys−NH2、
D−His−Lys−Tyr−D−Phe−Glu−D−Asp−D−His−D−Lys−Arg−Trp−NH2、
Ala−D−Phe−D−Arg−Tyr−Lys−D−Trp−His−D−Tyr−Gly−Phe、
Tyr−D−His−Phe−D−Arg−Asp−Lys−D−Arg−His−Trp−D−His−Phe、
Phe−Phe−D−Tyr−Arg−Glu−Asp−D−Lys−Arg−D−Arg−His−Phe−NH2、
Phe−Tyr−Lys−D−Arg−Trp−His−D−Lys−D−Lys−Glu−Arg−D−Tyr−Thr、
Tyr−Asp−D−Lys−Tyr−Phe−D−Lys−D−Arg−Phe−Pro−D−Tyr−His−Lys、
Glu−Arg−D−Lys−Tyr−D−Val−Phe−D−His−Trp−Arg−D−Gly−Tyr−Arg−D−Met−NH2、
Arg−D−Leu−D−Tyr−Phe−Lys−Glu−D−Lys−Arg−D−Trp−Lys−D−Phe−Tyr−D−Arg−Gly、
D−Glu−Asp−Lys−D−Arg−D−His−Phe−Phe−D−Val−Tyr−Arg−Tyr−D−Tyr−Arg−His−Phe−NH2、
Asp−Arg−D−Phe−Cys−Phe−D−Arg−D−Lys−Tyr−Arg−D−Tyr−Trp−D−His−Tyr−D−Phe−Lys−Phe、
His−Tyr−D−Arg−Trp−Lys−Phe−D−Asp−Ala−Arg−Cys−D−Tyr−His−Phe−D−Lys−Tyr−His−Ser−NH2、
Gly−Ala−Lys−Phe−D−Lys−Glu−Arg−Tyr−His−D−Arg−D−Arg−Asp−Tyr−Trp−D−His−Trp−His−D−Lys−Asp、
Thr−Tyr−Arg−D−Lys−Trp−Tyr−Glu−Asp−D−Lys−D−Arg−His−Phe−D−Tyr−Gly−Val−Ile−D−His−Arg−Tyr−Lys−NH2、
(atn)Dapがβ−アントラニロイル−L−α,β−ジアミノプロピオン酸である、Dmt−D−Arg−Phe−(atn)Dap−NH2、
Aldがβ−(6’−ジメチルアミノ−2’−ナフトイル)アラニンである、Dmt−D−Arg−Ald−Lys−NH2、
Aldがβ−(6’−ジメチルアミノ−2’−ナフトイル)アラニンである、Dmt−D−Arg−Phe−Lys−Ald−NH2、
(dns)Dapがβ−ダンシル−L−α,β−ジアミノプロピオン酸である、Dmt−D−Arg−Phe−(dns)Dap−NH2、
D−Arg−Tyr−Lys−Phe−NH2、及び
D−Arg−Tyr−Lys−Phe−NH2のうちの1つ以上を含む。
(i)水素、
(ii)直鎖または分枝鎖C1〜C6アルキルであって、
R3、R4、R5、R6、R7、R8、R9、R10、R11、及びR12は各々独立して、
(i)水素、
(ii)直鎖または分枝鎖C1〜C6アルキル、
(iii)C1〜C6アルコキシ、
(iv)アミノ、
(v)C1〜C4アルキルアミノ、
(vi)C1〜C4ジアルキルアミノ、
(vii)ニトロ、
(viii)ヒドロキシル、
(ix)クロロ、フルオロ、ブロモ、及びヨードを含むハロゲンから選択され、
nは1〜5の整数である。
(i)水素、
(ii)直鎖または分枝鎖C1〜C6アルキルであって、
R3及びR4は各々独立して、
(i)水素、
(ii)直鎖または分枝鎖C1〜C6アルキル、
(iii)C1〜C6アルコキシ、
(iv)アミノ、
(v)C1〜C4アルキルアミノ、
(vi)C1〜C4ジアルキルアミノ、
(vii)ニトロ、
(viii)ヒドロキシル、
(ix)クロロ、フルオロ、ブロモ、及びヨードを含むハロゲンから選択され、
R5、R6、R7、R8、及びR9は各々独立して、
(i)水素、
(ii)直鎖または分枝鎖C1〜C6アルキル、
(iii)C1〜C6アルコキシ、
(iv)アミノ、
(v)C1〜C4アルキルアミノ、
(vi)C1〜C4ジアルキルアミノ、
(vii)ニトロ、
(viii)ヒドロキシル、
(ix)クロロ、フルオロ、ブロモ、及びヨードを含むハロゲンから選択され、
nは1〜5の整数である。
芳香族−カチオン性−芳香族−カチオン性(式III)
カチオン性−芳香族−カチオン性−芳香族(式IV)
芳香族−芳香族−カチオン性−カチオン性(式V)
カチオン性−カチオン性−芳香族−芳香族(式VI)
式中、芳香族は、Phe(F)、Tyr(Y)、Trp(W)、及びシクロへキシルアラニン(Cha)からなる群から選択される残基であり、カチオン性は、Arg(R)、Lys(K)、ノルロイシン(Nle)、及び2−アミノ−ヘプタン酸(Ahe)からなる群から選択される残基である。
1.少なくとも1個の正味の正電荷、
2.最低で3個のアミノ酸、
3.最大で約20個のアミノ酸、
4.3pmがr+1以下の最大数である、正味の正電荷の最小数(pm)とアミノ酸残基の総数(r)との関係、及び
5.aが1である場合にptも1であり得ることを除いて、2aがpt+1以下の最大数である、芳香族基の最小数(a)と正味の正電荷の総数(pt)との関係を有する。
ミトコンドリア透過性遷移(MPT)を受けているミトコンドリアの数を減少させるか、または哺乳動物の切除された臓器におけるミトコンドリア透過性遷移を予防するか、またはコレステロール誘発性ミトコンドリア機能不全を特徴とする症状、状態、もしくは疾患を治療するための方法を提供する。本方法は、有効量の芳香族カチオン性ペプチドを切除された臓器に投与することを含み、この有効量の芳香族カチオン性ペプチドは、
少なくとも1個の正味の正電荷、
最低で3個のアミノ酸、
最大で約20個のアミノ酸、
3pmがr+1以下の最大数である、正味の正電荷の最小数(pm)とアミノ酸残基の総数(r)との関係、及び
aが1である場合にptも1であり得ることを除いて、2aがpt+1以下の最大数である、芳香族基の最小数(a)と正味の正電荷の総数(pt)との関係を有する。
少なくとも1個の正味の正電荷、
最低で3個のアミノ酸、
最大で約20個のアミノ酸、
3pmがr+1以下の最大数である、正味の正電荷の最小数(pm)とアミノ酸残基の総数(r)との関係、及び
aが1である場合にptも1であり得ることを除いて、3aがpt+1以下の最大数である、芳香族基の最小数(a)と正味の正電荷の総数(pt)との関係を有する。
H−Phe−D−Arg Phe−Lys−Cys−NH2、
D−Arg−Dmt−Lys−Trp−NH2、
D−Arg−Trp−Lys−Trp−NH2、
D−Arg−Dmt−Lys−Phe−Met−NH2、
H−D−Arg−Dmt−Lys(NαMe)−Phe−NH2、
H−D−Arg−Dmt−Lys−Phe(NMe)−NH2、
H−D−Arg−Dmt−Lys(NαMe)−Phe(NMe)−NH2、
H−D−Arg(NαMe)−Dmt(NMe)−Lys(NαMe)−Phe(NMe)−NH2、
D−Arg−Dmt−Lys−Phe−Lys−Trp−NH2、
D−Arg−Dmt−Lys−Dmt−Lys−Trp−NH2、
D−Arg−Dmt−Lys−Phe−Lys−Met−NH2、
D−Arg−Dmt−Lys−Dmt−Lys−Met−NH2、
H−D−Arg−Dmt−Lys−Phe−Sar−Gly−Cys−NH2、
H−D−Arg−Ψ[CH2−NH]Dmt−Lys−Phe−NH2、
H−D−Arg−Dmt−Ψ[CH2−NH]Lys−Phe−NH2、
H−D−Arg−Dmt−LysΨ[CH2−NH]Phe−NH2、ならびに
H−D−Arg−Dmt−Ψ[CH2−NH]Lys−Ψ[CH2−NH]Phe−NH2、
Tyr−D−Arg−Phe−Lys−NH2、
2′,6′−Dmt−D−Arg−Phe−Lys−NH2、
Phe−D−Arg−Phe−Lys−NH2、
Phe−D−Arg−Dmt−Lys−NH2、
D−Arg−2′6′Dmt−Lys−Phe−NH2、
H−Phe−D−Arg−Phe−Lys−Cys−NH2、
Lys−D−Arg−Tyr−NH2、
D−Tyr−Trp−Lys−NH2、
Trp−D−Lys−Tyr−Arg−NH2、
Tyr−His−D−Gly−Met、
Tyr−D−Arg−Phe−Lys−Glu−NH2、
Met−Tyr−D−Lys−Phe−Arg、
D−His−Glu−Lys−Tyr−D−Phe−Arg、
Lys−D−Gln−Tyr−Arg−D−Phe−Trp−NH2、
Phe−D−Arg−Lys−Trp−Tyr−D−Arg−His、
Gly−D−Phe−Lys−Tyr−His−D−Arg−Tyr−NH2、
Val−D−Lys−His−Tyr−D−Phe−Ser−Tyr−Arg−NH2、
Trp−Lys−Phe−D−Asp−Arg−Tyr−D−His−Lys、
Lys−Trp−D−Tyr−Arg−Asn−Phe−Tyr−D−His−NH2、
Thr−Gly−Tyr−Arg−D−His−Phe−Trp−D−His−Lys、
Asp−D−Trp−Lys−Tyr−D−His−Phe−Arg−D−Gly−Lys−NH2、
D−His−Lys−Tyr−D−Phe−Glu−D−Asp−D−His−D−Lys−Arg−Trp−NH2、
Ala−D−Phe−D−Arg−Tyr−Lys−D−Trp−His−D−Tyr−Gly−Phe、
Tyr−D−His−Phe−D−Arg−Asp−Lys−D−Arg−His−Trp−D−His−Phe、
Phe−Phe−D−Tyr−Arg−Glu−Asp−D−Lys−Arg−D−Arg−His−Phe−NH2、
Phe−Tyr−Lys−D−Arg−Trp−His−D−Lys−D−Lys−Glu−Arg−D−Tyr−Thr、
Tyr−Asp−D−Lys−Tyr−Phe−D−Lys−D−Arg−Phe−Pro−D−Tyr−His−Lys、
Glu−Arg−D−Lys−Tyr−D−Val−Phe−D−His−Trp−Arg−D−Gly−Tyr−Arg−D−Met−NH2、
Arg−D−Leu−D−Tyr−Phe−Lys−Glu−D−Lys−Arg−D−Trp−Lys−D−Phe−Tyr−D−Arg−Gly、
D−Glu−Asp−Lys−D−Arg−D−His−Phe−Phe−D−Val−Tyr−Arg−Tyr−D−Tyr−Arg−His−Phe−NH2、
Asp−Arg−D−Phe−Cys−Phe−D−Arg−D−Lys−Tyr−Arg−D−Tyr−Trp−D−His−Tyr−D−Phe−Lys−Phe、
His−Tyr−D−Arg−Trp−Lys−Phe−D−Asp−Ala−Arg−Cys−D−Tyr−His−Phe−D−Lys−Tyr−His−Ser−NH2、
Gly−Ala−Lys−Phe−D−Lys−Glu−Arg−Tyr−His−D−Arg−D−Arg−Asp−Tyr−Trp−D−His−Trp−His−D−Lys−Asp、ならびに
Thr−Tyr−Arg−D−Lys−Trp−Tyr−Glu−Asp−D−Lys−D−Arg−His−Phe−D−Tyr−Gly−Val−Ile−D−His−Arg−Tyr−Lys−NH2、
(atn)Dapがβ−アントラニロイル−L−α,β−ジアミノプロピオン酸である、Dmt−D−Arg−Phe−(atn)Dap−NH2、
(dns)Dapがβ−ダンシル−L−α,β−ジアミノプロピオン酸である、Dmt−D−Arg−Phe−(dns)Dap−NH2、
Aldがβ−(6’−ジメチルアミノ−2’−ナフトイル)アラニンである、Dmt−D−Arg−Ald−Lys−NH2、
Aldがβ−(6’−ジメチルアミノ−2’−ナフトイル)アラニン及びD−Arg−Tyr−Lys−Phe−NH2である、Dmt−D−Arg−Phe−Lys−Ald−NH2、ならびに
D−Arg−Tyr−Lys−Phe−NH2のうちの1つ以上を含む。
(a)非極性アミノ酸:Ala(A) Ser(S) Thr(T) Pro(P) Gly(G) Cys(C)、
(b)酸性アミノ酸:Asn(N) Asp(D) Glu(E) Gln(Q)、
(c)塩基性アミノ酸:His(H) Arg(R) Lys(K)、
(d)疎水性アミノ酸:Met(M) Leu(L) Ile(I) Val(V)、及び
(e)芳香族アミノ酸:Phe(F) Tyr(Y) Trp(W) His(H)。
表5.ペプチド類似体の例
表6.オピオイド受容体作動薬活性を有するペプチド類似体
Dap=ジアミノプロピオン酸
Dmt=ジメチルチロシン
Mmt=2′−メチルチロシン
Tmt=N,2′,6′−トリメチルチロシン
Hmt=2′−ヒドロキシ,6′−メチルチロシン
dnsDap=β−ダンシル−L−α,β−ジアミノプロピオン酸
atnDap=β−アントラニロイル−L−α,β−ジアミノプロピオン酸
Bio=ビオチン
ペプチド合成
コレステロール
脂質
芳香族カチオン性ペプチドの予防的及び治療的使用
ニーマンピック病
電子移動における芳香族カチオン性ペプチド
投与の形態及び有効用量
併用療法
一般的方法
実施例1.コレステロールは用量依存的にシトクロムcペルオキシダーゼ活性を増加させる。
実施例2.芳香族カチオン性ペプチドは、用量依存的様式でコレステロール誘発性シトクロムcペルオキシダーゼ活性を阻害する。
実施例3.芳香族カチオン性ペプチドは、コレステロールのシトクロムc減少に与える影響を緩和する。
実施例4.D−Arg−2′,6′−Dmt−Lys−Phe−NH2(SS−31)ペプチドは、シトクロムcのコレステロール誘発性構造変化を阻害する。
実施例5.芳香族カチオン性ペプチドとコレステロール−シトクロムc複合体との間の相互作用。
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均等物
Claims (25)
- コレステロール誘発性ミトコンドリア機能不全を特徴とする疾患を患う対象を治療するための方法であって、
治療的有効量の芳香族カチオン性ペプチドまたはその薬学的に許容される塩を前記対象に投与することを含む、前記方法。 - 前記芳香族カチオン性ペプチドが、2′,6′−Dmt−D−Arg−Phe−Lys−NH2(SS−02)、Phe−D−Arg−Phe−Lys−NH2(SS−20)、及びD−Arg−2′,6′−Dmt−Lys−Phe−NH2(SS−31)からなる群から選択される1つ以上のペプチドを含む、請求項1に記載の方法。
- 前記塩が、酢酸塩、酒石酸塩、またはトリフルオロ酢酸塩である、請求項1に記載の方法。
- 前記ペプチドが、D−Arg−2′,6′−Dmt−Lys−Phe−NH2(SS−31)を含む、請求項1に記載の方法。
- 前記疾患が、ニーマンピック病である、請求項1に記載の方法。
- 治療が、ニーマンピック病の1つ以上の症状を軽減または改善することを含み、前記ニーマンピック病の症状が、四肢を動かすことの困難(ジストニア)、脾臓及び肝臓の肥大(肝脾腫大症)、認知症、不明瞭で不規則な発語(構音障害)、不調和嚥下(嚥下障害)、転倒につながり得る筋緊張の突然の喪失(脱力発作)、振戦、眼を上下に動かすことの困難(垂直核上性注視麻痺)、運動失調、食欲減退、腹部膨満、血小板減少症、黄疸、疼痛、髄腔の拡大、皮質骨の薄化、寛骨の歪み、発作、眼内のサクランボ赤色斑点、ならびに睡眠関連障害からなる群から選択される1つ以上の症状である、請求項5に記載の方法。
- 前記芳香族カチオン性ペプチドが、経口、非経口、静脈内、皮下、経皮、局所、または吸入投与される、請求項1に記載の方法。
- コレステロール誘発性ミトコンドリア機能不全を特徴とする疾患を患う対象におけるカルジオリピン酸化を減少させるための方法であって、
有効量の芳香族カチオン性ペプチドまたはその薬学的に許容される塩を前記対象に投与することを含む、前記方法。 - 前記芳香族カチオン性ペプチドが、2′,6′−Dmt−D−Arg−Phe−Lys−NH2(SS−02)、Phe−D−Arg−Phe−Lys−NH2(SS−20)、及びD−Arg−2′,6′−Dmt−Lys−Phe−NH2(SS−31)からなる群から選択される1つ以上のペプチドを含む、請求項8に記載の方法。
- 前記塩が、酢酸塩、酒石酸塩、またはトリフルオロ酢酸塩である、請求項8に記載の方法。
- 前記芳香族カチオン性ペプチドが、経口、非経口、静脈内、皮下、経皮、局所、または吸入投与される、請求項8に記載の方法。
- 前記疾患が、ニーマンピック病である、請求項8に記載の方法。
- 前記方法が、ニーマンピック病の1つ以上の症状を軽減または改善することを含み、前記症状が、四肢を動かすことの困難(ジストニア)、脾臓及び肝臓の肥大(肝脾腫大症)、認知症、不明瞭で不規則な発語(構音障害)、不調和嚥下(嚥下障害)、転倒につながり得る筋緊張の突然の喪失(脱力発作)、振戦、眼を上下に動かすことの困難(垂直核上性注視麻痺)、運動失調、食欲減退、腹部膨満、血小板減少症、黄疸、疼痛、髄腔の拡大、皮質骨の薄化、寛骨の歪み、発作、眼内のサクランボ赤色斑点、ならびに睡眠関連障害である、請求項12に記載の方法。
- コレステロール誘発性ミトコンドリア機能不全を特徴とする疾患を患う対象におけるコレステロール誘発性シトクロムcペルオキシダーゼ活性を減少させるための方法であって、
有効量の芳香族カチオン性ペプチドまたはその薬学的に許容される塩を前記対象に投与することを含む、前記方法。 - 前記芳香族カチオン性ペプチドが、2′,6′−Dmt−D−Arg−Phe−Lys−NH2(SS−02)、Phe−D−Arg−Phe−Lys−NH2(SS−20)、及びD−Arg−2′,6′−Dmt−Lys−Phe−NH2(SS−31)からなる群から選択される1つ以上のペプチドを含む、請求項14に記載の方法。
- 前記塩が、酢酸塩、酒石酸塩、またはトリフルオロ酢酸塩である、請求項14に記載の方法。
- 前記芳香族カチオン性ペプチドが、経口、非経口、静脈内、皮下、経皮、局所、または吸入投与される、請求項14に記載の方法。
- 前記疾患が、ニーマンピック病である、請求項14に記載の方法。
- 前記方法が、ニーマンピック病の1つ以上の症状を軽減または改善することを含み、前記症状が、四肢を動かすことの困難(ジストニア)、脾臓及び肝臓の肥大(肝脾腫大症)、認知症、不明瞭で不規則な発語(構音障害)、不調和嚥下(嚥下障害)、転倒につながり得る筋緊張の突然の喪失(脱力発作)、振戦、眼を上下に動かすことの困難(垂直核上性注視麻痺)、運動失調、食欲減退、腹部膨満、血小板減少症、黄疸、疼痛、髄腔の拡大、皮質骨の薄化、寛骨の歪み、発作、眼内のサクランボ赤色斑点、ならびに睡眠関連障害である、請求項18に記載の方法。
- コレステロール誘発性ミトコンドリア機能不全を特徴とする疾患を患う対象におけるコレステロール誘発性構造損傷からシトクロムcを保護するための方法であって、
有効量の芳香族カチオン性ペプチドまたはその薬学的に許容される塩を前記対象に投与することを含む、前記方法。 - 芳香族カチオン性ペプチドが、2′,6′−Dmt−D−Arg−Phe−Lys−NH2(SS−02)、Phe−D−Arg−Phe−Lys−NH2(SS−20)、及びD−Arg−2′,6′−Dmt−Lys−Phe−NH2(SS−31)からなる群から選択される1つ以上のペプチドを含む、請求項20に記載の方法。
- 前記塩が、酢酸塩、酒石酸塩、またはトリフルオロ酢酸塩である、請求項20に記載の方法。
- 前記芳香族カチオン性ペプチドが、経口、非経口、静脈内、皮下、経皮、局所、または吸入投与される、請求項20に記載の方法。
- 前記疾患が、ニーマンピック病である、請求項20に記載の方法。
- 前記方法が、ニーマンピック病の1つ以上の症状を軽減または改善することを含み、前記症状が、四肢を動かすことの困難(ジストニア)、脾臓及び肝臓の肥大(肝脾腫大症)、認知症、不明瞭で不規則な発語(構音障害)、不調和嚥下(嚥下障害)、転倒につながり得る筋緊張の突然の喪失(脱力発作)、振戦、眼を上下に動かすことの困難(垂直核上性注視麻痺)、運動失調、食欲減退、腹部膨満、血小板減少症、黄疸、疼痛、髄腔の拡大、皮質骨の薄化、寛骨の歪み、発作、眼内のサクランボ赤色斑点、ならびに睡眠関連障害である、請求項24に記載の方法。
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