JP6093756B2 - 損なわれたエネルギー処理障害およびミトコンドリア欠損症 - Google Patents
損なわれたエネルギー処理障害およびミトコンドリア欠損症 Download PDFInfo
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- JP6093756B2 JP6093756B2 JP2014508487A JP2014508487A JP6093756B2 JP 6093756 B2 JP6093756 B2 JP 6093756B2 JP 2014508487 A JP2014508487 A JP 2014508487A JP 2014508487 A JP2014508487 A JP 2014508487A JP 6093756 B2 JP6093756 B2 JP 6093756B2
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Description
関連出願の相互参照
本出願は、引用によりその全体が明示的に本明細書に組み込まれる、2011年4月26日に出願された米国仮特許出願第61/479,288号の優先権の利益を主張する。
特定の疾患、特に、損なわれたエネルギー処理障害およびミトコンドリア欠損症を治療するための、同位体修飾された多価不飽和脂肪酸(「PUFA」)および他の修飾されたPUFA。
酸化ストレスは、ミトコンドリア病、神経変性疾患、先天性代謝異常、糖尿病、眼疾患、腎疾患、肝疾患、および心疾患などの様々な疾患に関与している。具体的には、そのような疾患としては、損なわれたエネルギー処理障害およびミトコンドリア欠損症が挙げられるが、これらに限定されるものではない。
いくつかの実施形態は、損なわれたエネルギー処理障害またはミトコンドリア欠損症の進行を治療または阻害する方法を提供し、これは、有効量の多価不飽和物質を損なわれたエネルギー処理障害またはミトコンドリア欠損症を有して治療を必要とする患者へ投与することを含み、ここで、多価不飽和物質は、1つ以上の結合が酸化に対して安定化されるように化学的に修飾されており、そして、前記1つ以上の安定化された結合を含む多価不飽和物質またはその多価不飽和代謝物が、投与後に患者の体内に取り込まれることを特徴とする。
本明細書で使用する場合、略語は以下のように定義される:
αLnn:α−リノレン酸
4−HHEまたはHHE:4−ヒドロキシヘキサ−2−エナール
4−HNEまたはHNE:4−ヒドロキシノン−2−エナール
AA:アラキドン酸
AcOH:酢酸
ALA:α−リノレン酸
AMVN:2,2’−アゾビス(2,4−ジメチルバレロニトリル)
BD:双極性障害
D:重水素化
D1:モノ重水素化
D2:ジ重水素化
D2−LA:ジ重水素化リノール酸
D3:トリ重水素化
D4:テトラ重水素化
D5:ペンタ重水素化
D6:ヘキサ重水素化
DAD:糖尿病と難聴
DHA:ドコサヘキサエン(22:6;n−3)酸
DMF:ジメチルホルムアミド
DS:ダウン症候群
EPA:エイコサペンタエン(20:5;n−3)酸
EtOAc:酢酸エチル
EtOH:エタノール
FA:Friedreich運動失調症
FAME:脂肪酸メチルエステル
HPMC:6−ヒドロキシ−2,2,5,7,8−ペンタメチルベンゾクロマン
H−PUFA:非重水素化多価不飽和脂肪酸
IP:腹腔内
IR:赤外線
KIE:動力学的同位体効果
LA:リノール酸
LDL:低密度リポタンパク質
LHON:Leber遺伝性視神経萎縮症
MELAS:ミトコンドリア脳筋症・乳酸アシドーシス・脳卒中症候群
MERRF:赤色ぼろ線維・ミオクローヌスてんかん症候群
MIDD:母系遺伝性の糖尿病と難聴
MNGIE:ミトコンドリア神経胃腸脳筋障害
MVEC:微小血管内皮細胞
NARP:神経障害・運動失調・網膜色素変性症・眼瞼下垂
NINCDS:神経/伝達障害と脳卒中
Ox−Phos:酸化的リン酸化
PUFA(s):多価不飽和脂肪酸(複数も可)
RIN:開始速度
ROS:活性酸素種
ROX:酸化速度
RPE:網膜色素上皮細胞
SNOMED:医学の体系化された命名法
TDMS:毒性データ管理システム
TH:チロシンヒドロキシラーゼ
THF:テトラヒドロフラン
TLC:薄層クロマトグラフィー
V−SMOW:ウィーン標準平均海水
WT:野生型
X−ALD:X連鎖性副腎白質ジストロフィー
YPD:1%バクト−酵母エキス、2%バクト−ペプトン、および2%デキストロースを含む培地
遺伝的突然変異(ミトコンドリアDNAと核DNAの両方における)ならびに環境要因は、ミトコンドリア障害の原因となり得る。ミトコンドリア欠損症またはミトコンドリア呼吸不全疾患は、ミトコンドリア膜に生じるミトコンドリア呼吸不全などのミトコンドリア膜成分の酸化によって引き起こされる疾患および障害を含む。膜の機能性は、全体的なミトコンドリア機能にとって重要である。酸化的リン酸化(OX−Phos)経路は、リノール酸含有リン脂質のカルジオリピンが豊富であるミトコンドリア内膜に豊富に見られる。ROS処理におけるどんな不均衡も、この膜や他の膜のPUFAの自動酸化の増加をこのようにもたらし、反応性カルボニル化合物のレベルの増加を引き起こし得る。これらのいくつかは、脱共役タンパク質−2(UCP−2)、アポトーシス、その他などの活性化/非活性化などの多数のプロセスを開始、アップレギュレートおよびダウンレギュレートすることができる。かなりの数の疾患が、ミトコンドリア機能障害に関連している。これらの疾患としては、コエンザイムQ欠損症;糖尿病および難聴(DAD)、ならびに母系遺伝性の糖尿病および難聴(MIDD);Friedreich運動失調症(FA);Leber先天性黒内障;Leber遺伝性視神経萎縮症(LHON);Leigh症候群;ミトコンドリア脳筋症・乳酸アシドーシス・脳卒中(MELAS)症候群;ミトコンドリア神経胃腸脳筋障害(MNGIE);赤色ぼろ線維・ミオクローヌスてんかん症候群(MERRF);筋神経遺伝性胃腸脳障害(MNGIE)および神経障害;神経障害・運動失調・網膜色素変性症・眼瞼下垂(NARP);視覚神経障害と眼筋麻痺;Wolff−Parkinson−White症候群と他の心筋症;X連鎖性副腎白質ジストロフィー(X−ALD);ならびに筋骨格系の疾患(脂質筋疾患、慢性疲労、線維筋痛症候群);腎臓疾患(Fanconi症候群および糸球体腎症);血液疾患(Pearson症候群);および脳疾患(偏頭痛、発作、および脳卒中)が挙げられるが、これらに限定されない。Santosら、Antioxidants & Redox Signaling(2010),13:5,651−690;Meierら、J.Neurol.(2011)PMID:21779958;Marobbioら、Mitochondrion(2011)PMID:21782979;Orsucciら、Curr.Med.Chem.(2011)18:26,4053−64;Lynchら、Arch.Neurol.(2010)67:8,941−947;Schultzら、J.Neurol.(2009)256 補遺1:42−5;Drinkardら、Arch.Phys.Med.Rehabil.(2010)91:7,1044−1050;Bergerら、Brain Pathol.(2010)20:4,845−856;Singhら、Brain Pathol.(2010)20:4,838−844;Lopez−Erauskinら、Ann Neurol.(2011)70,84−92を参照のこと。これらと他のミトコンドリア病は、ROSレベルを増加させ、当然の結果として、脂質などの細胞成分への損傷の増加を持続させる(McKenzie Mら、Neurochem Res 2004;2:589−600)。例えば、脊髄および他の組織における初期の酸化的損傷は、X−ALDの神経変性の根拠となる脂質およびアミノ酸過酸化バイオマーカーを用いて観察されている(Fourcade S.ら、Human Mol Genetics 2008;17:1762−1773)。
ダウン症候群(DS)
DS(21番染色体の3染色体)は、アルツハイマー病に似た、早期老化や精神遅滞と関連している。また、自己免疫疾患や白内障の発生率も上昇し、DSに罹患した個体の酸化ストレスの増加を指向する(Jovanovic SVら、Free Rad.Biol.Med.1998;25: 1044−1048)。21番染色体は、銅/亜鉛SODおよびアミロイドβ−ペプチドをコードし、したがって、DSはこれらの遺伝子産物と代謝物のオーバーフローによって、特にカタラーゼに対するSODの割合の増加が、過剰のH2O2を伴って特徴付けられる(Sinet PM.Ann.NY Acad.Sci.1982;396:83−94)。DSを有する個体では、タンパク質と脂質酸化のマーカー(MDA、HNE、その他)、および終末糖化および脂質酸化産物が、著しく増加している(Busciglio J,Yankner BA.Nature 1995;378:776−779;Odetti Pら、Biochem.Biophys.Res.Comm.1998;243:849−851)。ミトコンドリア機能障害はまた、ダウン症候群の認知症の病因と関連している。Coskunら、Journal of Alzheimer’s Disease(2010)20,S293−S310。DSにおける酸化ストレスの重要性は、抗酸化剤を用いることにより、酸化の副作用を低減する広範囲にわたる試みをもたらした;しかし、最近のランダム化試験では、抗酸化サプリメントの有効性の証拠は認められなかった(Ellis JMら、Brit.Med.J.2008;336:594−597)。ダウン症候群の対象は、標準的な染色体検査で識別することができる。
PUFAは、神経発達や統合失調症などのいくつかの精神障害に影響を及ぼすことが知られている。DHA、エイコサペンタエン酸(EPA)およびAAは、この点に関して特に重要である。統合失調症では、EPAの補給といくつかの症状の改善との間に正の相関関係がある(Luzon−Toro Bら、Neurol.Psychiatr.Brain Res.2004;11:149−160)。統合失調症とBDの両方において、酸化ストレスとHNEレベルの顕著な増加がある(Wang JFら、Bipolar Disorders 2009;11:523−529)。シナプス機能不全は、AD、ALS、PDなどの神経病理における早期病原性事象であることが知られている(LoPachin RMら、 Neurotoxicol.2008;29:871−882)。このシナプス毒性の分子メカニズムは、知られていないが、公開された証拠は、これらの疾患が、酸化ストレス、PUFAの過酸化(図1)、およびアクロレインや4−HNEなどのα,β−不飽和カルボニル誘導体の後続の遊離を含む共通の病態生理学的カスケードによって特徴付けられることを示唆している。
自閉症は、原因不明の発達障害のファミリーである。この障害は、行動異常、発育異常、神経病理学的異常および感覚異常によって特徴付けられ、通常は2〜10歳の間に診断され、ピーク有病率は5〜8歳の小児で観察される。酸化ストレスに対抗することができないことは、自閉症の病態を促進するものとして提案されている(Bowersら、“Glutathione pathway gene variation and risk of autism spectrum disorders”;J.Neurodev.Disord.;2011;3月5日、公開電子書籍フォーマット)。確かに、酸化ストレスへの脆弱性の増加は、その障害の1つの統一概念と考えられてきた(Ratajczak.“Theoretical Aspectes of Autism:Biomarkers−A Review”J.Immunotoxicol.2011;8(1):80−94)。さらに、異常なミトコンドリアの代謝もその障害の共通の分子基盤として確認されている(Lintasら、“Genome−wide expression studies in Autism spectrum disorder,Rett syndrome,and Down Syndrome”Neurobiol Dis.2010年12月2日 公開電子書籍フォーマット)。研究はまた、自閉症患者が、年齢がマッチする対照に比べて、PUFAレベルを含む著しく異なる脂肪酸レベルを有することを示している(El−Ansaryら、“Plasma fatty acids as diagnostic markers in autistic patients from Saudi Arabia.”Lipids in Health and Disease 2011,10:62,2011年4月21日にオンライン上で公開)。
ハンチントン病(HD)は、運動障害、精神障害、認知機能障害からの進行性障害につながる選択的神経変性によって特徴付けられる神経変性疾患である。HDはハンチンチン遺伝子のシトシン−アデニン−グアニン(CAG)反復伸長に起因し、転写障害、興奮毒性、酸化的損傷、炎症、アポトーシス、およびミトコンドリア機能不全の関与により、神経機能障害と最終的な細胞死を引き起こす突然変異タンパク質をもたらす。酸化ストレス関連損傷は、タンパク質とデオキシリボ核酸(DNA)と一緒に、脂質に発生する。ペルオキシソーム増殖因子活性化受容体γコアクチベータ−1α(PGC−1α)の損なわれた発現および機能はまた、その疾患に関与している。PGC−1αの欠損は、酸化ストレスへの脆弱性、および線条体変性を増加させる。この疾患における酸化ストレスの重要性をさらに支持し、抗酸化剤は、HDのトランスジェニックマウスモデルにおいて疾患の進行を遅らせるのに有効である。また、ROSおよびそのような種によって引き起こされる損傷は、HDにおけるニューロン喪失の主な要因として認識されている。Johriら、Biocehmica et Biophysica Acta(2011),doi:10.1016/j/bbadis.2011.11.014;Pattenら、Journal of Alzheimer’s Disease(2010)20:S357−S367を参照のこと。
いくつかの実施形態では、同位体修飾された多価不飽和脂肪酸または模倣物は、化学的に、または1つもしくは複数の同位体、例えば13Cおよび/もしくは重水素を用いた補強によって安定化されている、天然に存在するPUFAと構造的な類似性を有する化合物を指す。一般に、重水素が補強に使用される場合、メチレン基上の1つまたは両方の水素が補強され得る。
11,11−ジジュウテロ−シス,シス−9,12−オクタデカジエン酸(11,11−ジジュウテロ−(9Z,12Z)−9,12−オクタデカジエン酸;D2−LA);および11,11,14,14−テトラジュウテロ−シス,シス,シス−9,12,15−オクタデカトリエン酸(11,11,14,14−テトラジュウテロ−(9Z,12Z,15Z)−9,12,15−オクタデカトリエン酸;D4−ALA)である。いくつかの実施形態では、前記位置は、重水素化に加えて、炭素−13によって、それぞれ天然に存在する存在量レベルを超える同位体存在量のレベルでさらに補強され得る。PUFA分子におけるすべての他の炭素−水素結合は、場合により天然存在量レベル以上で重水素および/または炭素−13を含有することができる。
いくつかの実施形態では、本明細書に開示された化合物は、併用して投与される。例えば、いくつかの実施形態では、2つ、3つ、4つ、および/または5つ以上の安定化化合物が一緒に投与される。いくつかの実施形態では、安定化化合物は、ほぼ同様な量で投与される。他の実施形態では、安定化化合物は、異なる量で投与される。例えば、混合物中の2種以上の化合物のいずれか1つは、混合物の約1%〜約99%、混合物の約5%〜約95%、混合物の約10%〜約90%、混合物の約15%〜約85%、混合物の約20%〜約80%、混合物の約25%〜約75%、混合物の約30%〜約70%、、混合物の約35%〜約65%、混合物の約40%〜約60%、混合物の約40%〜約60%、混合物の約45%〜約55%、および/または混合物の約50%に相当し得る。他の実施形態では、混合物中の2種以上の化合物のいずれか1つは、混合物の約5%、約10%、約15%、約20%、約25%、約30%、約35%、約40%、約45%、約50%、約65%、約60%、約65%、約70%、約75%、約80%、約85%、約90%、約95%、または100%に相当し得る。
式中、R1およびR2は、独立して、−C1−C4アルキル、−C1−C4ハロアルキル、−CN、−F、−Cl、−Brおよび−Iから選択され;R3は、−C1−C4アルキル、−C1−C4ハロアルキル、−CN、−F、−Cl、および−Iから選択され、そして、R20は、独立して、−C1−C20アルキル、−C1−C20アルケニル、−C1−C20アルキニル、および少なくとも1つの2重結合と少なくとも1つの3重結合を有する−C1−C20から選択される。
などの化合物:
式中、mは−C1−C20アルキル、−C1−C20アルケニル、−C1−C20アルキニル、または少なくとも1つの2重結合および少なくとも1つの3重結合を含む−C1−C20であり、対イオンは、薬学的に許容され得るアニオンである。
トリグリセリドは、植物油および動物性脂肪の主成分であることがよく知られている。また、トリグリセリドは、グリセロールと3つの脂肪酸から誘導されるエステル化合物であることが知られている。トリグリセリドは、エステル結合を加水分解し、脂肪酸とグリセロールを放出するリパーゼなどの酵素によって代謝される。確かに、この代謝は、脂肪酸を放出し、それは、その後、脂肪酸輸送蛋白質を介して細胞によって取り込まれ得る。種々の疾患を治療するのに有用であるPUFAおよびPUFA模倣物は、患者への投与のために、トリグリセリド、ジグリセリド、および/またはモノグリセリドなどの脂肪に配合することができると考えられる。
いくつかの実施形態では、化合物は、約0.01mg/kg〜約1000mg/kg、約0.1mg/kg〜約100mg/kg、および/または約1mg/kg〜約10mg/kgで投与される。他の実施形態では、化合物は、約0.01mg/kg、約0.1mg/kg、約1.0mg/kg、約5.0mg/kg、約10mg/kg、約25mg/kg、約50mg/kg、約75mg/kg、約100mg/kg、約150mg/kg、約200mg/kg、約300mg/kg、約400mg/kg、約500mg/kg、および/または約1000mg/kgで投与される。
1Hと13Cスペクトルの特徴的エリアは、すべての値がppm単位である。(パネルA)11位のリノール酸の重水素化は、1Hと13CのNMRスペクトルのピークの消失によって確認される。δH2.764におけるピークの消失は、H原子(1H NMR)の不存在に起因するものと予想される。δC25.5におけるピークの消失は、核オーバーハウザー効果の組み合わせ、およびこの特定炭素原子の、リノール酸の重水素形における2つの重水素原子による5重線への分裂によるものである。(パネルB)1H NMRスペクトルは、部位特異的重水素化α−リノレン酸のC11およびC14位における水素原子が、一致し(δH2.801)、このように、いずれかの部位(11,11−H2,14,14−D2または11,11−D2,14,14−H2)における重水素化がこのピークの積分において50%の減少につながり、一方、両方の部位(11,11,14,14−D4)の重水素化は、δH2.801でのピークの完全な消失につながることを示している。しかし、13C NMR実験は、C11位またはC14位に対して観察されたピークは、小さいが検出可能な差によって分離されるので、3つの重水素化形態を明らかに区別することができる。したがって、C11またはC14のどちらかの位置での重水素化は、δC25.68またはδC25.60のそれぞれのピーク消失につながり、一方、両方の部位での重水素化は、2つの対応するピークの消失につながる。
Q−レス酵母(coqの変異体)は、脂肪酸のインビボでの自動酸化を評価するための理想的なシステムを提供する。コエンザイムQ(ユビキノンまたはQ)は、小さな脂溶性抗酸化剤としてだけでなく、ミトコンドリア内膜の呼吸鎖における電子シャトルとして機能する。10個のS.cerevisiae遺伝子(COQ1〜COQ10)は、コエンザイムQの生合成および機能、そして呼吸不全の結果の消去にも必要である(Tran UC,Clarke CF.Mitochondrion 2007;7S,S62)。coq酵母変異体は、PUFAの自動酸化生成物に非常に感受性であることが示された(Do TQら、PNAS USA 1996;93:7534−7539;Poon WW,Do TQ,Marbois BN,Clarke CF.Mol.Aspects Med.1997;18,s121)。S.cerevisiaeは、PUFAを産生しないが(Paltauf F,Daum G.Meth.Enzymol.1992;209:514−522)、それらは、外的に提供されるとき、PUFAを利用することができ、それらの内容物を操作させることができる(Paltauf F,Daum G.Meth.Enzymol.1992;209:514−522)。Q−レス(coq2、coq3、およびcoq5)酵母変異体の1%未満は、リノレン酸の4時間処理後、生存可能である(Do TQら、PNAS USA 1996;93:7534−7539;Poon WW,Do TQ,Marbois BN,Clarke CF.Mol.Aspects Med.1997;18,s121)。対照的に、この処理に供された野生型(親の遺伝的背景は、W303−1B株である)細胞の70%は生存可能のままである。Q−レス酵母はまた、容易に自動酸化する他のPUFA(例えばアラキドン酸など)には過敏であるが、モノ不飽和オレイン酸による処理に対して、野生型親株と同じように振る舞う(Do TQら、PNAS USA 1996;93:7534−7539)。cor1またはatp2変異体酵母(それぞれ、bc1複合体またはATP合成酵素のどちらかを欠いている)は、PUFA処理に対して野生型の耐性を示すため、Q−レス酵母変異体の過敏性は、呼吸不全の二次的影響ではない(Do TQら、PNAS USA 1996;93:7534−7539;Poon WW,Do TQ,Marbois BN,Clarke CF.Mol.Aspects Med.1997;18,s121)。
酵母はPUFAを合成しないが、しかし、それらは外因的に供給されるリノール酸とリノレン酸の取り込みを行う(Avery SVら、Applied Environ.Microbiol.1996;62,3960;Howlett NGら、Applied Environ.Microbiol.1997;63,2971)。従って、酵母はまた、外的に供給されたD4−リノレン酸を取り込みそうである。しかし、リノレン酸およびD4−リノレン酸への異なる感受性は、自動酸化よりもむしろ細胞内への組込みの違いに起因し得る可能性がある。このケースに該当するかどうかを試験するために、この脂肪酸の取り込みの程度が監視された。まず、C18:1、C18:3,D4−C18:3、およびC17:0(内部標準として使用される)の脂肪酸メチルエステル(FAME)の分離の条件が決定された。図5に示されるGC−MSクロマトグラムは、これらの脂肪酸メチルエステル標準の分離と検出感度の両方を確立する。
LAおよびD2−LAの酸化過程における酸素消費の動力学を、ガラス毛管マイクロ体積計を用いて調べた(図7)。酸化速度ROXは、[O2]トレースの傾きとして測定された。開始速度RINは、基準阻害剤としてのHPMC(「6−ヒドロキシ−2,2,5,7,8−ペンタメチルベンゾクロマン」)による阻害剤方法により測定した。RINを、阻害された酸化の誘導期tIND:RIN=2・[HPMC]/tINDから算出した。0.71MのLAの酸化速度(図7)は、6.1×10−6M/sであることが判明した。プロセスが0.23mMの連鎖破壊抗酸化剤HPMCにより阻害されたとき、誘導期間tINDの持続時間は、約48分であり、RIN値は、約0.16×10−6M/sであった。これらのデータから算出した速度論的連鎖長は、ν=ROX/RIN=38±3であった。このデータに基づいて、LAの計算された酸化力は、0.0215±0.008M−0.5s−0.5(n=5)であった(Gosgrave J.Pら、Lipids,1987,22,299−304)。D2−LAについては、ROXの0.18×10−6M/秒への減少が観察された(図7)。LAとは対照的に、HPMCの添加は、ROXの減少や任意の検出可能な誘導期間の出現をもたらすことはなかった(データは示されていない)。後者は、RINの直接的な決定を排除する。LAのそれと匹敵するD2−LA酸化に対するRIN値については、D2−LA酸化が、連鎖プロセスではなかったということになる(ν=0.18×10−6/0.16×10−6、およそ1.1)。LAとD2−LAに対するROXの比較から、推定動力学的同位体効果(「KIE」)は、約6.1×10−6/0.18×10−6、およそ35であった。同様なKIEは、Triton X−100水性ミセル中でのLAと11,11−d2−LAの酸化過程で測定された(データは示さていない)。比較目的のため、理論的なKIEは、25℃で6.9である。Carpenter,“Determination of Organic Reaction Mechanisms”(John Wiley&Sons,1984),p.89を参照されたい。
ありそうなインビボ条件をシミュレーションするために、D2−LAとLAとの混合物の酸化の動力学について検討した(図8)。実験において、LA+11,11−d2−LAの濃度は、0.775Mであり;AMVNの濃度は、0.0217Mであり;そして、反応は37℃で行われた。その結果、1.10±0.08×10−7M/秒のRINを得た。また、混合物の酸化速度は、非相加的であり、個々の化合物についてのROXの加算値よりもはるかに低いことが分かった。驚くべきことに、D2−LAは、本質的に自動酸化に対して非重水素化LAを「保護」する。定量的に同様の効果が、非重水素化リノール酸メチルと11,11−D2−LAの混合物の酸化の過程で観察された(データは示されない)。これらの結果は、D2−LAによる非重水素化LAの部分的置換でさえPUFA過酸化を実質的に遅らせる可能性を示唆している。
実施例13に記載の結果が、Q−レスcoq3酵母株およびLAとD2−LAの異なる比率を用いてインビボで再現された(図9)。野生型、酵母Q−レスcoq3、あるいは呼吸不全cor1ヌル変異体を、200μΜのLAおよびD2−LAの存在下、図9に示されるように、PUFAの異なる割合でインキュベーションした。0.2OD/mlで始まる系列希釈液(1:5)をYPD固体平板培地上にスポットした。また、ゼロ時間未処理の対照を利用し、その結果を図9の左上に示す。増殖は30℃においてであった。結果は、D2−LAの約10〜15%が、LAの毒性を取り消すのに十分な、最小限の量であったことを示している。モノ−重水素化PUFA、11,11−D,H−LAとの同様のインキュベーション処理は、処理3時間後の細胞生存率において、検出可能な減少をもたらさなかった(データは示されていない)。これらの結果は、D2−LAおよび11,11−D,H−LAの両方が脂質過酸化に対して耐性であったことを示唆している。
実施例14に記載の実験プロトコルはまた、Q−レスcoq3酵母株(図10)およびALAのD4−ALAに対する異なる割合を用いてインビボで再現された。野生型、酵母Q−レスcoq3、あるいは呼吸不全cor1ヌル変異体を、200μΜのALAおよびD4−Lnn(リノレン酸)の存在下、図10に示されるように、PUFAの異なる割合でインキュベーションした。0.2OD/mlで始まる系列希釈液(1:5)をYPD固体平板培地上にスポットした。増殖は30℃においてであった。結果はD2−Lnnの約15〜20%が、ALAの毒性を取り消すのに十分な、最小限の量であったことを示している。さらに、結果は、酵母細胞によって取り込まれたPUFAの含量は、添加された割合を大まかに反映し、酵母細胞が提供されたPUFAを区別しないことを示唆している。
微小血管内皮(MVEC)、網膜色素上皮(RPE)および網膜神経細胞(網膜神経節細胞)を含むいくつかの細胞型を、細胞培養における生存率について試験した。細胞を、水素化(対照)または重水素化D2−リノール酸(ω−6;LA)およびD4−リノレン酸(ω−3;ALA)(20μM;ω−6対ω−3の比率:1:1または2:1)のいずれかを含有する培地中で、72時間維持した。細胞へのPUFAの取り込みを、GCによって監視した(図11)。MVECへのPUFAの取り込みを示す表1によれば、PUFAは、細胞によって容易に取り込まれることが示された。
より長期の投与パラダイム(すなわち、3週間の食餌の置き換え)による、H−PUFAおよびD−PUFAを補充したマウスの血清の化学的分析(UC Davisで実施した)では、H−PUFA/D−PUFA生理食塩水処理マウスについて腎機能、肝機能、血液脂質等の主要バイオマーカーにおいて差は明らかにならなかった。この例では、D−PUFAは、D2−リノール酸:D4−リノレン酸の2:1混合物である。
顕微鏡的変化は、最も具体的な組織分布的な形態学的診断によってコード化され、体系化医療名称(SNOMED)と国立毒性プログラムの毒性データ管理システム(TDMS)の用語マニュアルが、ガイドラインとして使用された。データは、Labcat(登録商標)病理モジュール4.30に記録された。4段階の採点システム(最小、軽度、中等度、および顕著)が、等級付け可能な変化を定めるのに用いられた。
WTマウスは、1ケージあたり12匹(雌から分離した雄)を収容し、6%総脂肪を含むAIN93食餌をペレットとして90日間、自由摂取(通常は5〜6g/日)させた。その総脂肪の約10%は、D2−LA/D4−ALA(第1群)、D2−LA/ALA(第2群)、またはLA/ALA(対照群)の1:1混合物から構成された。動物を屠殺し、臓器を回収し、保存剤を使用せずに分析前に低温で保存した。脂質画分を分離し、前処理し、対照としてLA、D2−LA、ALAおよびD4−ALAを使用して、標準プロトコルに従ってLC−MSにより分析した。
いくつかの容易に測定可能な臨床マーカーは、ミトコンドリア障害を有する患者の代謝状態を評価するために有用である。これらのマーカーは、マーカーのレベルが病的な値から健康な値に移動するので、特定の治療の効力の指標として使用することもできる。これらの臨床マーカーは、限定されるものではないが、全血、血漿、脳脊髄液、または脳室液のいずれかにおける乳酸(ラクテート)レベル;全血、血漿、脳脊髄液、または脳室液のいずれかにおけるピルビン酸(ピルベート)レベル;全血、血漿、脳脊髄液、または脳室液のいずれかにおけるラクテート/ピルベート比率;クレアチンリン酸レベル、NADH(NADH+H+)またはNADPH(NADPH+H+)レベル;NADまたはNADPレベル;ATPレベル;嫌気性閾値;還元型コエンザイムQ(CoQred)レベル;酸化型コエンザイムQ(CoQox)レベル;、総コエンザイムQ(CoQtot)レベル;酸化型チトクロームCレベル;還元型チトクロームCレベル;酸化型チトクロームC/還元型チトクロームC比率;アセト酢酸レベル、β−ヒドロキシ−ブチレートレベル、アセト酢酸/β−ヒドロキシ−ブチレート比率、8−ヒドロキシ−2’−デオキシグアノシン(8−OHdG)レベル;活性酸素種のレベル;ならびに酸素消費のレベル(VO2)、二酸化炭素産生レベル(VCO2)、および呼吸商(VCO2/VO2)などの1つ以上のエネルギーバイオマーカーを含む。これらの臨床マーカーのいくつかは、運動生理学研究所で常用手順で測定され、対象の代謝状態の簡便な評価を与えることができる。
同位体比質量分析法は、様々な組織のリン脂質膜へのD−PUFAの取り込みを確認するために使用することができる。食餌補給によってD2−LAおよびD4−ALAを送達する際、動物組織への取り込みは、脂質膜中の重水素組成の全体的増加の測定を可能にする同位体比質量分析技術を用いて監視され得、このようにして、D2−LA、D4−ALA、およびこれらの化合物から誘導される任意の他のPUFAの取り込みについて報告される。この方法を使用して、動物組織へのD−PUFAの実質的な取り込みを検出することができる。例えば、マウスに、唯一のPUFA源としてD−PUFA(D2−LA、D4−ALA、およびD2−LAとD4−ALA両方の1:1の組み合わせの0.01、0.1、1.0、10.0、および100mg/kg)またはH−PUFA(LA、ALA、およびLAとALA両方の1:1の組み合わせの0.01、0.1、1.0、10.0、および100mg/kg)を6日間補給し、既知の酸化剤や生理食塩水に急激にさらし、さらに6日間、同じ食餌を続けた。脳、肝臓、心臓、肺組織を切除し、対照マウスと試験化合物で処理したマウスからのホモジネート試料を、上記実施例7で説明したように、重水素含有量について分析する。D2−LAおよびD4−ALAは、分析される組織および細胞中に見られることが予想される。
D−PUFA(D2−LA、D4−ALA、およびD2−LAとD4−ALA両方の1:1の組み合わせの0.01、0.1、1.0、10.0、および100mg/kg)またはH−PUFA(LA、ALA、およびLAとALA両方の1:1の組み合わせの0.01、0.1、1.0、10.0、および100mg/kg)は、L−ブチオニン−(S,R)−スルホキシイミン(BSO)の添加によるストレス付加によってストレスがかけられた自閉症症候群障害(ASD)線維芽細胞をレスキューする能力について、Jauslinら、Hum.Mol.Genet.11(24):3055(2002),Jauslinら、FASEB J.17:1972−4(2003)および国際特許出願WO2004/003565(これらは、引用により本明細書に組み込まれる)に記載の通り、スクリーニングされる。ASD線維芽細胞は、グルタチオン(GSH)合成酵素の特異的阻害剤であるL−ブチオニン−(S,R)−スルホキシイミン(BSO)によるGSHのデノボ合成の阻害に過敏である可能性が高い(Jauslinら、Hum.Mol.Genet.11(24):3055(2002))。BSO伝達性細胞死は、当然、D−PUFAの投与により防止および/または緩和される。
抗精神病薬の投薬を受けていない統合失調症の患者を試験のために選択する。食餌PUFA源をコントロールしながら、D−PUFA(D2−LA、D4−ALA、およびD2−LAとD4−ALA両方の1:1の組み合わせの0.01、0.1、1.0、10.0、および100mg/kg)またはH−PUFA(LA、ALA、およびLAとALA両方の1:1の組み合わせの0.01、0.1、1.0、10.0、および100mg/kg)を6ヶ月の期間にわたって毎日投与する。毎週、患者を、統合失調症の症状発現の頻度および持続時間について評価する。さらに、血液試料を毎週採取し、上記バイオマーカーなどの酸化ストレスのバイオマーカーを測定する。D2−LAおよびD4−ALAは、統合失調症の症状発現の頻度および/または持続時間を減少させ、酸化ストレスに関連したバイオマーカーのレベルを低減することが予想される。
ダウン症候群皮質ニューロン培養物は、当業界で公知である。D−PUFA(D2−LA、D4−ALA、およびD2−LAとD4−ALA両方の1:1の組み合わせの0.01、0.1、1.0、10.0、および100μM)またはH−PUFA(LA、ALA、およびLAとALA両方の1:1の組み合わせの0.01、0.1、1.0、10.0、および100μM)を、DS皮質培養物に施し、公知の方法を用いて細胞生存率を24時間、48時間、および72時間後に測定する。D2−LAおよびD4−ALAは、DS皮質ニューロンの生存率を向上させることが予想される。
m−線維芽細胞(FrdaL3/L−;h−I54F)は、両方のフラタキシン対立遺伝子を欠損し、当該疾患に関連するヒトのフラタキシン(I154F)の突然変異型を過剰発現する。FAC(クエン酸鉄アンモニウム)およびBSO(グルタチオン合成阻害剤のブチオニンスルホキシイミン)による細胞の処理は、細胞生存率の減少をもたらした。細胞を48ウェルプレートに播種し、それぞれ48時間および24時間、FACおよびBSOで処理した。H/D−PUFAをBSO処理の2時間後に添加した。実験の終わりに、細胞生存率を、Promega Cell−Glowキットによって評価し、%生存率(図22)としても表記される任意発光単位(ALU)で測定した。図22において、NTは未処理を表す;Fは、クエン酸鉄アンモニウムを表す;Bは、ブチオニンスルホキシイミンを表す;CCは、アッセイ中の最終濃度を0.5%にするために使用する担体対照のDMSO(ジメチルスルホキシド)を表す;およびIDBは、イデベノンを表す。結果は、D−LA投与による生存率の用量依存的レスキューを示した。同様の結果(図示せず)はまた、上記の実験プロトコルによりD−ALAを使用して得られた。
本発明はその具体的な実施形態を参照して説明したが、様々な変更を行うことができ、均等物が本発明の真の精神および範囲から逸脱することなく置き換えることができることを、当業者は理解すべきである。これは、本明細書に記載された利点と機能のすべてを提供するものではない実施形態を含む。さらに、多くの修正が、特定の状況、材料、組成物、プロセス、プロセス工程または複数の工程を本発明の目的、精神および範囲に適合させるためになされることができる。全てのそのような修正は、本明細書に添付の特許請求の範囲に含まれるものである。従って、本発明の範囲は、添付の特許請求の範囲を参照することによってのみ定義される。
Claims (19)
- 損なわれたエネルギー処理障害またはミトコンドリア欠損症を治療または阻害する際に経口使用するための組成物であって、
前記組成物は、下記式(3)を有する重水素化された多価不飽和の脂肪酸または脂肪酸エステルを含む:
前記重水素化された多価不飽和の脂肪酸または脂肪酸エステルが、投与後に患者の体内に取り込まれる;および
前記重水素化された多価不飽和の脂肪酸または脂肪酸エステルが、前記患者に投与される多価不飽和の脂肪酸または脂肪酸エステルの総量の約10%〜50%を含む、組成物。 - 前記重水素化された多価不飽和の脂肪酸または脂肪酸エステルが、前記患者に投与される、請求項1に記載の組成物。
- 前記重水素化された多価不飽和の脂肪酸または脂肪酸エステルが、少なくとも1個の13C原子を含み、ここで、前記の少なくとも1個の13C原子が、前記13C原子の天然の存在量レベルより顕著に上のレベルで存在する、請求項1に記載の組成物。
- 前記重水素化された脂肪酸または脂肪酸エステルが、患者に投与される脂肪酸または脂肪酸エステルの総量の約10%〜30%を含む、請求項1に記載の組成物。
- 前記重水素化された脂肪酸または脂肪酸エステルが、患者に投与される脂肪酸または脂肪酸エステルの総量の約20%以上を含む、請求項1に記載の組成物。
- 患者の細胞または組織が、天然に存在する多価不飽和の脂肪酸または脂肪酸エステルの自動酸化を防止するために、前記重水素化された脂肪酸または脂肪酸エステルの十分な濃度を維持する、請求項1に記載の組成物。
- 前記重水素化された脂肪酸または脂肪酸エステルが、ω−3脂肪酸もしくはω−3脂肪酸エステル、またはω−6脂肪酸もしくはω−6脂肪酸エステルである、請求項1に記載の組成物。
- 前記重水素化された脂肪酸または脂肪酸エステルが、11,11−D2−リノレン酸、14,14,D2−リノレン酸、11,11,14,14−D4−リノレン酸、11、11−D2−リノール酸、14,14−D2−リノール酸、11,11,14,14−D4−リノール酸、11−D−リノレン酸、14−D−リノレン酸、11,14−D2−リノレン酸、11−D−リノール酸、14−D−リノール酸、および11,14−D2−リノ−ル酸からなる群から選択される、請求項7に記載の組成物。
- 前記重水素化された脂肪酸または脂肪酸エステルが、プロ−ビス−アリル位でさらに重水素化される、請求項7に記載の組成物。
- 前記脂肪酸エステルが、エチルエステルである、請求項2に記載の組成物。
- 前記脂肪酸エステルが、トリグリセリド、ジグリセリド、またはモノグリセリドである、請求項2に記載の組成物。
- 抗酸化剤をさらに含む、請求項2に記載の組成物。
- 前記抗酸化剤が、コエンザイムQ、イデベノン、ミトキノン、ミトキノール、ビタミンC、またはビタミンEである、請求項12に記載の組成物。
- 前記重水素化された脂肪酸または脂肪酸エステルが、リノール酸である、請求項1に記載の組成物。
- 前記重水素化された脂肪酸または脂肪酸エステルが、リノレン酸である、請求項1に記載の組成物。
- 前記重水素化された脂肪酸または脂肪酸エステルが、アラキドン酸である、請求項1に記載の組成物。
- 前記重水素化された脂肪酸または脂肪酸エステルが、エイコサペンタエン酸である、請求項1に記載の組成物。
- 前記重水素化された脂肪酸または脂肪酸エステルが、ドコサヘキサエン酸である、請求項1に記載の組成物。
- 1つまたは複数のY1−YnがHである、請求項1に記載の組成物。
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KR102112087B1 (ko) | 2020-05-18 |
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JP2017071633A (ja) | 2017-04-13 |
JP6322264B2 (ja) | 2018-05-09 |
IL229018A0 (en) | 2013-12-31 |
KR20190107152A (ko) | 2019-09-18 |
US20190046644A1 (en) | 2019-02-14 |
AU2019257541B2 (en) | 2021-08-26 |
IL229018B (en) | 2020-09-30 |
US20140044692A1 (en) | 2014-02-13 |
US10058612B2 (en) | 2018-08-28 |
WO2012148927A3 (en) | 2013-01-17 |
AU2012249918A1 (en) | 2013-12-12 |
KR20140033060A (ko) | 2014-03-17 |
AU2017225070B2 (en) | 2019-08-15 |
WO2012148927A2 (en) | 2012-11-01 |
EP2701696A4 (en) | 2014-10-15 |
CA2834342C (en) | 2021-08-31 |
JP2014513099A (ja) | 2014-05-29 |
EP2701696A2 (en) | 2014-03-05 |
CA2834342A1 (en) | 2012-11-01 |
AU2012249918B2 (en) | 2017-06-15 |
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