JP6797117B2 - アンモニア降下療法を用いた肝星細胞活性化関連疾患の処置 - Google Patents
アンモニア降下療法を用いた肝星細胞活性化関連疾患の処置 Download PDFInfo
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- JP6797117B2 JP6797117B2 JP2017527742A JP2017527742A JP6797117B2 JP 6797117 B2 JP6797117 B2 JP 6797117B2 JP 2017527742 A JP2017527742 A JP 2017527742A JP 2017527742 A JP2017527742 A JP 2017527742A JP 6797117 B2 JP6797117 B2 JP 6797117B2
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Description
本出願は、35U.S.C.§119(e)の下で2014年11月24日出願の米国仮特許出願第62/083,814号に基づく優先権を主張し、その全体が参照により本明細書に明示的に組み込まれる。
本出願は、医薬化学、生化学、および医学の分野に関する。一態様は、アンモニア降下療法を用いた肝星細胞(HSC)活性化関連疾患の処置および/または予防に関する。
肝星細胞(HSC)は、肝臓の類洞周囲腔に見出される周皮細胞である。肝臓内では、星細胞は肝臓の構造的完全性を維持する上で重要な役割を果たし、線維症および肝臓がんの発症に関与している。正常な肝臓ではHSCは静止状態にある。肝臓が損傷を受けるとHSCが活性化状態に変わる場合がある。活性化された星細胞は、増殖性、収縮性、および走化性を特徴とする。HSCの活性化によって、様々な疾患、例えば、非アルコール性脂肪肝疾患(NAFLD)、線維性状態、および肝臓がんが引き起こされ得る。
本明細書で使用する場合、「対象」は、処置、観察、または実験の対象である動物を指す。「動物」としては、魚類、甲殻類、爬虫類、および特に哺乳類などの、冷血および温血の脊椎動物および無脊椎動物が挙げられる。「哺乳動物」としては、限定するものではないが、マウス;ラット;ウサギ;モルモット;イヌ;ネコ;ヒツジ;ヤギ;ウシ;ウマ;サル、チンパンジー、および類人猿、ならびに特にヒトなどの霊長類が挙げられる。
BDL=胆管結さつ
本明細書において、対象のアンモニアレベルを低下させるために用いることができる様々なアンモニア降下療法が開示される。例えば、対象のアンモニアレベルを低下させるために、1種または複数種のアンモニア降下剤を治療に用いることができる。本明細書で使用する場合、用語「アンモニア降下剤」は、対象のアンモニアレベルを低下させるために用いることができる物質を指す。アンモニア降下剤がアンモニアレベルを低下させる機構は様々であり得る。例えば、アンモニア降下剤は、対象におけるアンモニアの発生を減少させることによって、または、対象においてアンモニアを吸収すること、もしくは、結腸内にアンモニアを引き込み緩下剤効果によりアンモニアを除去することによって、またはこれらの任意の組み合わせによって、対象のアンモニアレベルを低下させることができる。いくつかの実施形態では、対象におけるアンモニアレベルは、対象の血液(例えば、血漿)中のアンモニアレベルであってよい。いくつかの実施形態では、アンモニア降下療法は、1種または複数種のアンモニア降下剤を対象に投与することを含む。
肝星細胞(HSC)は、肝臓生理学および線維形成、ならびに肝臓の構造的完全性の維持において重要な役割を果たす肝臓特異的間葉細胞である。HSCは一般にディッセ腔(space of Disse)に位置し、類洞内皮細胞および肝上皮細胞との密接な相互作用を維持している。HSCは、肝臓における多くの重要な機能を調整し、その機能不全は様々な病理学的状態と関連している。HSCは、肝臓の発生および再生の際、他の肝細胞種の分化、増殖および形態形成に影響を及ぼし得る。
いくつかの実施形態では、アンモニア降下剤(フェニル酢酸塩および/またはフェニル酪酸塩と組み合わせたオルニチンなど)は、医薬として許容される塩として投与される。用語「医薬として許容される塩」は、化合物の生物学的有効性および性質を保持しており、生物学的にもその他の点でも、医薬品における使用に有害でない塩を指す。多くの場合、本明細書に開示されるアンモニア降下剤は、アミノおよび/もしくはカルボキシル基またはそれに類似した基の存在により、酸および/または塩基塩を形成することができる。医薬として許容される酸付加塩は、無機酸および有機酸を用いて形成することができる。塩が誘導され得る無機酸としては、例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸などが挙げられる。塩が誘導され得る有機酸としては、例えば、酢酸、プロピオン酸、グリコール酸、ピルビン酸、シュウ酸、マレイン酸、マロン酸、コハク酸、フマル酸、酒石酸、クエン酸、安息香酸、桂皮酸、マンデル酸、メタンスルホン酸、エタンスルホン酸、p−トルエンスルホン酸、サリチル酸などが挙げられる。また、医薬として許容される塩は、無機および有機塩基を用いて形成することもできる。塩が誘導され得る無機塩基としては、例えば、ナトリウム、カリウム、リチウム、アンモニウム、カルシウム、マグネシウム、鉄、亜鉛、銅、マンガン、アルミニウムなどを含有する塩基が挙げられ;特に、アンモニウム、カリウム、ナトリウム、カルシウム、およびマグネシウム塩が好ましい。いくつかの実施形態では、本明細書に開示される化合物を無機塩基で処置すると、化合物から不安定な水素が失われ、Li+、Na+、K+、Mg2+、およびCa2+などの無機カチオンを含む塩形態が提供される。塩が誘導され得る有機塩基としては、例えば、第一級、第二級、および第三級アミン、天然に存在する置換アミンなどの置換アミン、環状アミン、塩基性イオン交換樹脂など、具体的にはイソプロピルアミン、トリメチルアミン、ジエチルアミン、トリエチルアミン、トリプロピルアミン、およびエタノールアミンが挙げられる。1987年9月11日公開の国際公開第87/05297号パンフレット、Johnstonら(その全体が参照により本明細書に組み入れられる)に記載されているように、多くのそのような塩は当該分野で既知である。
アンモニア降下剤(フェニル酢酸塩および/またはフェニル酪酸塩と組み合わせたオルニチンなど)は、医薬として許容される担体または希釈剤とともに投与用に製剤化することができる。アンモニア降下剤は、いくつかの実施形態では、製薬業界において通常行われるように、標準的な医薬として許容される担体(複数可)および/または賦形剤(複数可)とともに医薬品として製剤化することができる。製剤の実際の性質は、望まれる投与経路などのいくつかの要因に依存することになる。例えば、アンモニア降下剤(例えば、オルニチンならびにフェニル酢酸塩および/またはフェニル酪酸塩)は、経口、静脈内、胃内、血管内、または腹腔内投与用に製剤化することができる。その全体が参照により本明細書に組み込まれるRemington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005)に開示されるものなどの標準的な医薬製剤技術を用いることができる。
初代ヒト肝星細胞(hHSC)を培養した。hHSC増殖(BrdU)、代謝活性(MTSアッセイ)、生存率(ニュートラルレッド)、超微細構造変化(TE−M)、および遺伝子/タンパク質発現(q−PCR/ウェスタンブロット)に対するNH4Cl負荷(NH4Cl challenge)(24〜72時間にわたり0.1〜10mM)の影響を検討した。回復について試験するために、アンモニア処置細胞にグルタミンを補充し、また別の実験において、L−メチオニン−スルホキシミン(MSO−GS阻害剤)で前処置してグルタミン合成酵素(GS)の重要性を測定した。
28日間胆管結さつ(BDL)したラットを生理食塩水またはオルニチンフェニル酢酸で5日間処置した。終了時に門脈圧を測定し、検討のために組織を収集した。高アンモニア血症のBDLラットでは、線維形成性hHSC関連遺伝子(α−SMA、PDGFb−R、ミオシンIIA/IIB、およびCollI)の肝臓での発現が増加しており、eNOS活性およびDDAH−1が低く、門脈圧が高く、これらはいずれもオルニチンフェニル酢酸による処置によって改善された。
この実施例は、アンモニアがHSCに対して有害な形態学的および機能的効果をもたらし、HSCのアンモニア誘導性機能不全はアンモニア降下剤OPを用いることにより好転できることを示す。
この実施例では、初代ヒトHSC(hHSC)を単離し培養した。24〜72時間にわたるアンモニア負荷(50μM、100μM、300μM)の影響を同定するために、増殖(BrdU)、代謝活性(MTS)、形態(TEM、光学および免疫蛍光顕微鏡法)、HSC活性化マーカー、収縮能、および酸化状態の変化(ROS)を評価した。血漿アンモニアレベル、HSC活性化マーカー、門脈圧、および肝臓eNOS活性の変化を、高アンモニア血症のBDL動物で、およびそのOP処置後に定量した。
初代hHSCは、ロイヤルフリーホスピタルで手術を受けた患者から得た肝臓組織のくさび形切片からインフォームドコンセント(EC01.14−RF)を与えた後単離した。細胞は、ヒト肝臓用にWaugh MG, editor. Lipid Signaling Protocols, 2 ed. New York: Springer Science+Business Media; 2015. p. 203-212のRombouts K, Carloni V. Determination and characterization of tetraspanin-associated phosphoinositide-4 kinases in primary and neoplastic liver cells.に記載されるように改変したMederacke et al. (Nature Protocols 2015, 10:305-315)にしたがって単離した。簡潔には、10gのヒト全肝臓組織を、0.01%コラゲナーゼ、0.05%プロナーゼ、および0.001%DNアーゼIで、灌流を行わずに消化した。ホモジネートを100μmのセルストレーナーで濾過し、フロースルーを50×gで2分間4℃で遠心分離した。上清を洗浄後、11.5%Optiprep勾配を用いて1400×gで17分間4℃で勾配遠心分離を行った。最後に接触面を回収し洗浄した。hHSCSの純度は、CD140b(PDGFRベータ)、CD29(インテグリンベータ1)、およびサイトグロビン(CYGB)を検出することにより確立した。
すべての動物実験は、ユニヴァーシティ・カレッジ・ロンドンの動物保護に関する倫理委員会の承認を得て、英国動物科学的処置法1986年(UK Animals in Scientific Procedures Act 1986)の下で、内務省指針にしたがって実施した。この研究は、体重220〜250gの雄Sprague−Dawleyラット(Charles River UK、Margate、UK)で行った。
結果は、平均値±SEMとして表され、変数の一方向分析の後、適宜、DunnetまたはTukeyの多重比較事後検定を用いて比較した。P値≦0.05を有意とみなした。
アンモニアは、ヒト肝星細胞(hHSC)における細胞増殖および代謝をインビトロで用量依存的に低下させる。異なる濃度のアンモニアで72時間処置したhHSCは、細胞増殖(BrdUアッセイ)および代謝活性(MTSアッセイ)における有意な阻害を示した(図1A)。さらに、アンモニアによる細胞の長期処置は、細胞死検出ELISAを用いて評価されるとおり、hHSCにおいて細胞死を引き起こさなかった(図1B)。また、これらのアンモニア誘導性効果は、光学顕微鏡検査で認められる、細胞形態の用量依存的な大きな変化と一致した(図1C)。筋線維芽細胞様細胞として知られるhHSCは、完全培地および血清飢餓下で示されるように、リソソームが保持する色素であるニュートラルレッドで評価されるとおり、アンモニアで処置した場合、エンドリソソーム区画の脱調節(deregulation)の兆候とともに、形態が紡錘状線維芽細胞表現型に劇的に変化した(図1C)。hHSCは、mRNAおよびタンパク質レベルでグルタミン合成酵素(GS)を発現することが見出された。L−メチオニンスルホキシミン(GSの生化学的阻害剤であるMSO)による細胞の前処置と、それに続くアンモニアへの曝露は、MSO処置のみの場合と比べて、増殖および代謝活性をさらに阻害することはなかった。
この実施例は、NASHの動物モデルにおいて、オルニチントランスカルバミラーゼ(OTC)の遺伝子およびタンパク質の発現が変化し、その変化が、食餌の回復、および細菌転座の減少による動物の回復により改善できることを示す。この実施例はまた、NAFLD患者においてOTCの遺伝子発現が変化することを示している。
この実施例では2つの動物モデルを検討する:(i)SpragueDawleyラットを分割して、高脂肪および高コレステロールに富んだ食餌(HFHC食)、または高脂肪およびコレステロール含量を含まない標準食(標準食)のいずれかを16週まで給餌する;および、(ii)ラットにフルクトースを補充した高脂肪食(HFD+F食)を16週まで給餌する。
この実施例では、線維症/HCCのラットモデルを用いて、アンモニア低下剤OPがHCC発症のリスクを低減できるかどうかを決定する。
液体高脂肪食(HFD)(kcalの71%脂肪)を16週まで雄ラットに給餌することでラットにNAFLDを誘導する。ラットで最も一般的に使用されるNAFLDモデルの1つである肥満Zuckerラットを用意する。フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つと組み合わせたオルニチン、例えばOPを、HFDラットおよび肥満Zuckerラットに投与する。フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つと組み合わせたオルニチンの投与は、HFDラットおよび肥満Zuckerラットにおけるアンモニア濃度を低下させ、食餌誘導性NAFLDラットモデルおよびNAFLDの遺伝的ラットモデルにおけるNAFLDの進行を軽減させるのに有効であることが期待される。
液体高脂肪食(HFD)(kcalの71%脂肪)を3週間雄ラットに給餌することによってラットにNAFLDを誘導する。ラットで最も一般的に使用されるNAFLDモデルの1つである肥満Zuckerラットを用意する。食餌誘導性NAFLDラットモデルおよび遺伝的NAFLDラットモデルの両方において、ラットのオルニチントランスカルバモイラーゼを欠損させることにより(OTC欠損)、自然発症高アンモニア血症を操作する。OTC欠損ラットは、ラットのOTC遺伝子を変異または欠失させることによって作製する。食餌誘発性および遺伝的NAFLDラットモデルの両方において、ラットに高タンパク質食を与えることにより、誘導された高アンモニア血症を操作する。自然発症高アンモニア血症および誘導性高アンモニア血症のいずれも、NAFLDおよび線維症の進行を悪化させることが予想される。
液体高脂肪食(HFD)(kcalの71%脂肪)を3週間雄ラットに給餌することによってラットにNAFLDを誘導する。ラットで最も一般的に使用されるNAFLDモデルの1つである肥満Zuckerラットを用意する。HFDラットおよび肥満ラットに対して体重減少手術を実施する。体重減少手術は、食餌誘導性NAFLDラットモデルおよびNAFLDの遺伝的ラットモデルにおけるNAFLDの進行を軽減することが期待される。また、体重減少により、NAFLDラットモデルにおける肝臓の窒素処理、OTC遺伝子/タンパク質の発現および機能が改善されることも予想される。
本発明は次の実施態様を含む。
[1]肝星細胞(HSC)活性化関連疾患を処置する方法であって、それを必要とする対象に対してアンモニア降下療法を実施することを含む方法。
[2]
肝星細胞(HSC)活性化関連疾患の発症または進行を遅延させる方法であって、それを必要とする対象に対してアンモニア降下療法を実施することを含む方法。
[3]
アンモニア降下療法を実施することが、前記対象にアンモニア降下剤を投与することを含む、上記[1]または[2]に記載の方法。
[4]
前記アンモニア降下剤が、リン酸マグネシウム生成物(MGP)、グリセロールフェニル酪酸(GPB)、フェニル酢酸ナトリウム、フェニル酪酸ナトリウム(NaPBA)、グルタミン、安息香酸ナトリウム、L−アラビノース、緩下剤、抗生物質、フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つと組み合わせたオルニチン、またはそれらの任意の組み合わせを含む、上記[3]に記載の方法。
[5]
前記アンモニア降下剤が、フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つと組み合わせたオルニチンを含む、上記[3]に記載の方法。
[6]
前記オルニチンならびにフェニル酢酸塩およびフェニル酪酸塩の少なくとも1つの個々の医薬として許容される塩が前記対象に投与される、上記[5]に記載の方法。
[7]
フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つが、フェニル酢酸ナトリウムまたはフェニル酪酸ナトリウムとして投与される、上記[6]に記載の方法。
[8]
前記オルニチンが、遊離単量体アミノ酸またはその生理学的に許容される塩として投与される、上記[5]に記載の方法。
[9]
前記オルニチンおよびフェニル酢酸塩が、オルニチンフェニル酢酸として投与される、上記[5]に記載の方法。
[10]
前記投与が、経口、静脈内、腹腔内、胃内、または血管内投与である、上記[3]から[9]のいずれかに記載の方法。
[11]
前記投与が静脈内投与である、上記[10]に記載の方法。
[12]
前記投与が経口投与である、上記[10]に記載の方法。
[13]
前記HSC活性化関連疾患が、非アルコール性脂肪肝疾患(NAFLD)である、上記[1]から[12]に記載の方法。
[14]
前記NAFLDが非アルコール性脂肪性肝炎(NASH)である、上記[13]に記載の方法。
[15]
前記NAFLDが脂肪症である、上記[13]に記載の方法。
[16]
前記HSC活性化関連疾患が肝臓がんである、上記[1]から[12]に記載の方法。
[17]
前記HSC活性化関連疾患が線維性状態である、上記[1]から[12]に記載の方法。
[18]
前記線維性状態が肝臓線維症である、上記[17]に記載の方法。
[19]
前記対象が非アルコール性脂肪肝疾患(NAFLD)に罹患している、上記[16]から[18]のいずれかに記載の方法。
[20]
非アルコール性脂肪肝疾患(NAFLD)を予防する方法であって、それを必要とする対象に対してアンモニア降下療法を実施することを含む方法。
[21]
アンモニア降下療法を実施することが、前記対象にアンモニア降下剤を投与することを含む、上記[20]に記載の方法。
[22]
前記NAFLDが非アルコール性脂肪性肝炎(NASH)である、上記[20]または[21]に記載の方法。
[23]
前記NAFLDが脂肪症である、上記[20]または[21]に記載の方法。
[24]
前記アンモニア降下剤が、リン酸マグネシウム生成物(MGP)、グリセロールフェニル酪酸(GPB)、フェニル酢酸ナトリウム、フェニル酪酸ナトリウム(NaPBA)、グルタミン、安息香酸ナトリウム、L−アラビノース、緩下剤、抗生物質、フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つと組み合わせたオルニチン、またはそれらの任意の組み合わせを含む、上記[21]から[23]のいずれかに記載の方法。
[25]
前記アンモニア降下剤が、フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つと組み合わせたオルニチンを含む、上記[24]に記載の方法。
[26]
前記オルニチンならびにフェニル酢酸塩およびフェニル酪酸塩の少なくとも1つの個々の医薬として許容される塩が前記対象に投与される、上記[25]に記載の方法。
[27]
フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つが、フェニル酢酸ナトリウムまたはフェニル酪酸ナトリウムとして投与される、上記[26]に記載の方法。
[28]
前記オルニチンが、遊離単量体アミノ酸またはその生理学的に許容される塩として投与される、上記[25]に記載の方法。
[29]
前記オルニチンおよびフェニル酢酸塩が、オルニチンフェニル酢酸として投与される、上記[25]に記載の方法。
[30]
前記投与が、経口、静脈内、腹腔内、胃内、または血管内投与である、上記[21]から[29]のいずれかに記載の方法。
[31]
前記投与が静脈内投与である、上記[30]に記載の方法。
[32]
前記投与が経口投与である、上記[30]に記載の方法。
Claims (12)
- 肝星細胞(HSC)活性化関連疾患を処置するための組成物であって、前記HSC活性化関連疾患が、非アルコール性脂肪肝疾患(NAFLD)、肝臓がん又は線維性状態であり、
アンモニア降下剤を含む、組成物であって、
前記アンモニア降下剤が、フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つと組み合わせたオルニチンを含む、
組成物。 - 肝星細胞(HSC)活性化関連疾患の発症または進行を遅延させるための組成物であって、前記HSC活性化関連疾患が、非アルコール性脂肪肝疾患(NAFLD)、肝臓がん又は線維性状態であり、アンモニア降下剤を含む、組成物であって、
前記アンモニア降下剤が、フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つと組み合わせたオルニチンを含む、
組成物。 - 前記線維性状態が肝臓線維症である、請求項1又は2に記載の組成物。
- 非アルコール性脂肪肝疾患(NAFLD)を予防するための組成物であって、アンモニア降下剤を含み、前記アンモニア降下剤が、フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つと組み合わせたオルニチンを含む、
組成物。 - 前記NAFLDが非アルコール性脂肪性肝炎(NASH)である、請求項1、2又は4に記載の組成物。
- 前記NAFLDが脂肪症である、請求項1、2又は4に記載の組成物。
- 前記アンモニア降下剤が、前記オルニチンならびにフェニル酢酸塩およびフェニル酪酸塩の少なくとも1つの個々の医薬として許容される塩を含む、請求項1〜6のいずれか一項に記載の組成物。
- フェニル酢酸塩およびフェニル酪酸塩の少なくとも1つの医薬として許容される塩が、フェニル酢酸ナトリウムまたはフェニル酪酸ナトリウムを含む、請求項7に記載の組成物。
- 前記アンモニア降下剤が、オルニチンの遊離単量体アミノ酸またはその生理学的に許容される塩を含む、請求項1〜6のいずれか一項に記載の組成物。
- 前記アンモニア降下剤が、オルニチンフェニル酢酸を含む、請求項1〜6のいずれか一項に記載の組成物。
- 経口、静脈内、腹腔内、胃内、または血管内投与用である、請求項1〜10のいずれか一項に記載の組成物。
- 経口投与用である、請求項11に記載の組成物。
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