JP2021529169A - 統合失調症及び他の神経精神障害の治療方法 - Google Patents
統合失調症及び他の神経精神障害の治療方法 Download PDFInfo
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Abstract
Description
本開示は、K+取り込み障害を有するグリア細胞においてグリア細胞カリウム(K+)取り込みを回復させる方法に関する。これらの方法は神経精神状態に苦しむ対象を治療するのに好適である。
統合失調症は、妄想的思考、幻聴、及び認知障害を特徴とする精神障害であり、世界中の人口のおおまかに1%を冒すが、まだ十分に理解されていないままである(Allen et al.,”Systematic Meta−Analyses and Field Synopsis of Genetic Association Studies in Schizophrenia:The SzGene Database,”Nature Genetics,40:827−834(2008)(非特許文献1);Sawa及びSnyder,”Schizophrenia:Diverse Approaches to a Complex Disease,”Science,296:692−695(2002)(非特許文献2))。過去10年間で、多数の統合失調症関連遺伝子がグリア細胞の発達と生理に関与していることが明らかになっている(Yin et al.,”Synaptic Dysfunction in Schizophrenia,”Adv.Exp.Med.Biol.970:493−516(2012)(非特許文献3))。したがって、星状細胞及び希突起膠細胞の双方の機能障害が統合失調症の病因に関係している。特に星状細胞は、神経回路網の構造発達ならびに神経回路活動の調整の双方で必須の役割を有し、後者はグリア伝達物質の放出、シナプス密度の維持、及びシナプスのカリウムと神経伝達物質のレベルの調節を介する(Christopherson et al.,”Thrombospondins are Astrocyte−Secreted Proteins That Promote CNS Synaptogenesis”,Cell,120:421−433(2005)(非特許文献4);Chung et al.,”Astrocytes Mediate Synapse Elimination Through MEGF10 and MERTK Pathways”,Nature,504:394−400(2013)(非特許文献5);及びThrane et al.,”Ammonia Triggers Neuronal Disinhibition and Seizures by Impairing Astrocyte Potassium Buffering”,Nat.Med.19:1643−1648(2013)(非特許文献6))。しかしながら、統合失調症のような神経精神障害の発症において星状細胞の機能障害が担う役割は不明である。本開示は、当該技術分野におけるこの欠陥及び他の欠陥を克服することを目的とする。
本開示の第1の態様は、グリア細胞によるK+取り込みを回復させる方法に関するものであり、ここで、前記グリア細胞はK+取り込み障害を有する。この方法は、K+取り込み障害を有するグリア細胞に、前記グリア細胞によるK+取り込みを回復させるのに有効な条件下でRE1サイレンシング転写因子(REST)の阻害物質を投与することを含む。
本開示の第1の態様は、グリア細胞によるK+取り込みを回復させる方法に関するものであり、ここで、前記グリア細胞はK+取り込み障害を有する。この方法は、K+取り込み障害を有するグリア細胞に、前記グリア細胞によるK+取り込みを回復させるのに有効な条件下でRE1サイレンシング転写因子(REST)の阻害物質を投与することを含む。
のRESTヌクレオチド配列を標的とする、
、及び、
のRESTヌクレオチド配列を標的とする、
。
例示的なRNA RESTアプタマー
患者の識別、保護、及び試料採取。 人工多能性幹細胞(iPSC)由来のグリア前駆細胞(GPC)が由来する患者は、青年期初期に発症する統合失調症の重度障害の程度と診断された。すべての患者とその保護者は小児青年精神科医に同意し/承諾し、大学病院症例医療センターの施設内審査委員会の承認されたプロトコールの下でその後の方針の指定について盲検化された。治験責任医師は患者IDへのアクセスを有さなかった。
本試験で使用された細胞株は、参照によってその全体が本明細書に組み込まれるWindrem et al.,”Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia”,Cell Stem Cell,21:195−208.e6(2017)において以前記載され、公開された2017。本試験で追加された追加の操作、つまり、星状細胞の分化、及び結果として生じる分化した星状細胞によるK+取り込みの評価は、最も右側の2つの縦列に言及されている。
)を、ピューロマイシンのすぐ下流のベクターpTANK−EF1a−CoGFP−Puro−WPREにクローニングした。RESTのヒトcDNA(Stephen Elledgeからの贈与,Addgeneプラスミド41903)(参照によってその全体が本明細書組み込まれるWestbrook et al.,”SCFbeta−TRCP Controls Oncogenic Transformation and Neural Differentiation Through REST Degradation”,Nature,452:370−374(2008))は、ベクターpTANK−EF1a−IRES−mCherry−WPRE(参照によってその全体が本明細書組み込まれるBenraiss et al.,”Human Glia Can Both Induce and Rescue Aspects of Disease Phenotype in Huntington Disease”,Nat.Commun.7:11758(2016))のEF1aプロモーターの直後にクローニングした。レンチウイルスベクターは、レポーターmCherryと連動してRESTの発現を可能にした。
iPSCは、以前記載された(参照によってその全体が本明細書に組み込まれるWindrem et al.,”Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia”,Cell Stem Cell,21:195−208.e6(2017))ように、小児期に発症した統合失調症の患者から、ならびに既知の精神疾患のない健康な若年成人対照から得られた皮膚試料から作製した。年齢、性別、人種、診断及び投薬歴が細胞株識別子を伴っていたが、患者識別子は治療する精神科医以外の治験責任医師には用いることができなかった。手短に言えば、線維芽細胞を各試料から単離した。これらから、8つのhiPSC細胞株が患者試料と正常対照(5人の若年発症統合失調症患者及び3人の健康な性別が一致し年齢が類似した対照(表1))から導出された。iPSCは、Oct4、Sox2、Klf4及びc−Myc(参照によってその全体が本明細書に組み込まれるTakahashi et al.,”Induction of Pluripotent Stem Cells From Adult Human Fibroblasts by Defined Factors”,Cell,131:861−872(2007);Welstead et al.,”Generating iPS Cells From MEFS Through Forced Expression of Sox−2, Oct−4, c−Myc, and Klf4”,J.Vis.Exp.(14):734(2008))をコードする切除可能なloxPに挟まれたポリシストロン性hSTEMCCAレンチウイルス(参照によってその全体が本明細書に組み込まれるSomers et al.,”Generation of Transgene−Free Lung Disease−Specific Human Induced Pluripotent Stem Cells Using a Single Excisable Lentiviral Stem Cell Cassette”,Stem Cells,28:1728−1740(2010);Zou et al.,”Establishment of Transgene−Free Induced Pluripotent Stem Cells Reprogrammed From Human Stem Cells of Apical Papilla for Neural Differentiation”,Stem Cell Res.Ther.3:43(2012))を用いて生成した。細胞株はすべて、多能性遺伝子発現を評価するためにRNA配列決定及び免疫標識を用いて多能性として検証された。短縦列反復(STR)に基づくDNAフィンガープリントを用いて、各iPSC細胞株の独自性が親ドナー線維芽細胞と一致することを確認し、ゲノムの完全性を確認するために各細胞株を核型分析した。4番目のhiPSC対照細胞株であるC27(参照によってその全体が本明細書に組み込まれるChambers et al.,”Highly Efficient Neural Conversion of Human ES and iPS Cells by Dual Inhibition of SMAD Signaling”,Nature Biotechnology,27:275−280(2009))も用いてゲノムデータ及び表現型データのすべてが以前の研究(参照によってその全体が本明細書に組み込まれるWang et al.,”Human iPSC−Derived Oligodendrocyte Progenitor Cells Can Myelinate and Rescue a Mouse Model of Congenital Hypomyelination”,Cell Stem Cell,12:252−264(2013))と一致していることを確認した。
SCZ GPCの星状細胞分化の欠陥に対する分子付随物を同定するために、生体外にて154日から242日に及ぶ時点で3つの異なるCTR由来細胞株及び4つのSCZ由来細胞株からFACSによって選別したCD140a+GPCでRNA配列決定を実施した(参照によってその全体が本明細書に組み込まれるWindrem et al.,”Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia”,Cell Stem Cell,21:195−208.e6(2017))。Illumina HiSeq 2500プラットフォームでのRNA配列決定用のポリA選択によって、1試料あたり約4,500万の1×100bpの読み取りについてこれらの細胞からmRNAを単離した。元のカウントを分析して、5%FDR及びlog2変化倍率>1での疾患調節不全遺伝子を決定した。それによって、対照iPSC hGPCと比べてCD140aで選別したSCZ hGPCによって一貫して有意に差次的に発現された118個のmRNAが同定されていた(参照によってその全体が本明細書に組み込まれるWindrem et al.,”Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia”,Cell Stem Cell,21:195−208.e6(2017))。これらの中で、グリア系列の進行に関与する多数の遺伝子が正常な対照と比べてSCZ hGPCで下方調節されたということは、SCZ由来のグリア前駆細胞の固有の欠陥のせいで、星状膠細胞の分化がSCZでは細胞自律的に損なわれていたことを示唆している。
多数のカリウムチャネルをコードする遺伝子がSCZのグリアで調節不全になっているので、個々のカリウムチャネルのみを標的とする遺伝的手段を介してグリアのK+取り込みを調節することは困難である。この問題に対処するために、Biobase−Transfac分析が使用された。この分析は、共有する上流調節因子を明らかにする手段として、さまざまな遺伝子に共通の調節領域を同定するために開発された(Hu et al.,”Genome−Wide Identification of Transcription Factors and Transcription−Factor Binding Sites in Oleaginous Microalgae Nannochloropsis”,Sci.Rep.4:5454(2014)、これは参照によってその全体が本明細に組み込まれる)。これによって、SCZ関連グリア遺伝子の転写開始部位(TSS)から1kb以内の共有調節エレメントがデータセットで同定された。その意図は、これらの遺伝子を群として調節できる上流の転写因子を同定することだった。13ヌクレオチドのコンセンサス配列(CCNNGGTGCTGAA;SEQ ID NO:21)を用いて、すべての下方調節されたカリウムチャネル遺伝子のうちの大部分が、非神経細胞に作用して神経系遺伝子の発現を抑制する強力な転写リプレッサーであるニューロン制限サイレンシング因子(NRSF)REST(図3C)の標的であることが決定された(Hirabayashi及びGotoh,”Epigenetic Control of Neural Precursor Cell Fate During Development”,Nat.Rev.Neurosci.11:377−388(2010)、これは参照によってその全体が本明細に組み込まれる)。その上で、RNA配列決定データが照会され、それはCTR GPCと比べてSCZ GPCでRESTが実際に一貫して有意に上方調節されていることを明らかにした(Windrem et al.,”Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia”,Cell Stem Cell,21:195−208.e6(2017)、これは参照によってその全体が本明細書に組み込まれる)。qPCRを用いて、SCZのグリアによるREST発現の上方調節が一連の患者すべてで一貫していることを確認した(図6A)。その上で、統合失調症由来グリアにおけるRESTの上方調節、及びそれらに付随するエピジェネティックな修飾は、カリウムチャネル関連遺伝子の発現を抑制するのに十分である可能性があると仮定された。
Claims (58)
- K+取り込み障害を有するグリア細胞においてK+取り込みを回復させる方法であって、
K+取り込み障害を有する前記グリア細胞に、前記グリア細胞によるK+取り込みを回復させるのに有効な条件下でRE1−サイレンシング転写因子(REST)阻害物質を投与すること
を含む、前記方法。 - 前記グリア細胞がグリア前駆細胞である、請求項1に記載の方法。
- 前記投与することによって、グリア前駆細胞の星状細胞分化が回復する、請求項2に記載の方法。
- 前記グリア細胞が星状細胞である、請求項1に記載の方法。
- 前記REST阻害物質がバルプロ酸である、請求項1に記載の方法。
- 前記REST阻害物質がベンゾイミダゾール−5−カルボキサミド誘導体である、請求項1に記載の方法。
- 前記ベンゾイミダゾール−5−カルボキサミド誘導体が、2−(2−ヒドロキシ−フェニル)−1H−ベンゾイミダゾール−5−カルボン酸アリルオキシ−アミド(X5050)、または2−チオフェン−2−イル−1H−ベンゾイミダゾール−5−カルボン酸(2−エチル−ヘキシル)−アミド(X5917)である、請求項6に記載の方法。
- 前記REST阻害物質がピラゾールプロピオンアミド誘導体である、請求項1に記載の方法。
- 前記ピラゾールプロピオンアミド誘導体が、3−[1−(3−ブロモ−フェニル)−3,5−ジメチル−1H−ピラゾール−4−イル]−1−{4−[5−(モルホリン−4−カルボニル)−ピリジン−2−イル]−2−フェニル−ピペラジン−1−イル}−プロパン−1−オン(X38210)、または3−[1−(2,5−ジフルオロ−フェニル)−3,5−ジメチル−1H−ピラゾール−4−イル]−1−{4−[5−(モルホリン−4−カルボニル)−ピリジン−2−イル]−2−フェニル−ピペラジン−1−イル}−プロパン−1−オン(X38207)である、請求項8に記載の方法。
- 前記REST阻害物質が、RESTアンチセンスオリゴヌクレオチド、REST shRNA、REST siRNA、及びREST RNAアプタマーから成る群から選択される阻害性核酸分子である、請求項1に記載の方法。
- 前記REST阻害物質が抗REST抗体またはその抗原結合断片である、請求項1に記載の方法。
- K+取り込み障害を有する前記グリア細胞が、神経精神障害を有する対象のグリア細胞である、請求項1に記載の方法。
- 前記神経精神障害が統合失調症である、請求項12に記載の方法。
- 対象においてグリア細胞K+取り込みを回復させる方法であって、
グリア細胞K+取り込み障害を有する対象を選択すること、および
選択された前記対象に、グリア細胞K+取り込みを回復させるのに有効な条件下でRE1−サイレンシング転写因子(REST)阻害物質を投与すること
を含む、前記方法。 - 前記グリア細胞がグリア前駆細胞である、請求項14に記載の方法。
- 前記投与することが、前記対象におけるグリア前駆細胞の星状細胞分化を回復させるのに有効な条件下で行われる、請求項15に記載の方法。
- 前記グリア細胞が星状細胞である、請求項14に記載の方法。
- 前記投与することが、星状細胞K+恒常性を回復させるのに有効な条件下で行われる、請求項17に記載の方法。
- 前記REST阻害物質がバルプロ酸を含む、請求項14に記載の方法。
- 前記REST阻害物質がベンゾイミダゾール−5−カルボキサミド誘導体を含む、請求項14に記載の方法。
- 前記ベンゾイミダゾール−5−カルボキサミド誘導体が、2−(2−ヒドロキシ−フェニル)−1H−ベンゾイミダゾール−5−カルボン酸アリルオキシ−アミド(X5050)、または2−チオフェン−2−イル−1H−ベンゾイミダゾール−5−カルボン酸(2−エチル−ヘキシル)−アミド(X5917)である、請求項20に記載の方法。
- 前記REST阻害物質がピラゾールプロピオンアミド誘導体を含む、請求項14に記載の方法。
- 前記ピラゾールプロピオンアミド誘導体が、3−[1−(3−ブロモ−フェニル)−3,5−ジメチル−1H−ピラゾール−4−イル]−1−{4−[5−(モルホリン−4−カルボニル)−ピリジン−2−イル]−2−フェニル−ピペラジン−1−イル}−プロパン−1−オン(X38210)、または3−[1−(2,5−ジフルオロ−フェニル)−3,5−ジメチル−1H−ピラゾール−4−イル]−1−{4−[5−(モルホリン−4−カルボニル)−ピリジン−2−イル]−2−フェニル−ピペラジン−1−イル}−プロパン−1−オン(X38207)である、請求項22に記載の方法。
- 前記REST阻害物質が、RESTアンチセンスオリゴヌクレオチド、REST shRNA、REST siRNA、及びREST RNAアプタマーから成る群から選択される阻害性核酸分子を含む、請求項14に記載の方法。
- 前記REST阻害物質が抗REST抗体またはその抗原結合断片を含む、請求項14に記載の方法。
- 前記REST阻害物質が送達ビヒクル中にパッケージされる、請求項14に記載の方法。
- 前記送達ビヒクルがナノ粒子である、請求項26に記載の方法。
- 前記送達ビヒクルが、グリア細胞を標的とする部分を含む、請求項26に記載の方法。
- 前記選択された対象が、神経精神障害を有する、または神経精神障害のリスクを有する、請求項14に記載の方法。
- 前記神経精神障害が、統合失調症、自閉症スペクトラム症、及び双極性障害から成る群から選択される、請求項29に記載の方法。
- 前記神経精神障害が統合失調症である、請求項30に記載の方法。
- 前記投与することが、前記対象においてニューロンの興奮性を減らすのに有効な条件下で行われる、請求項14に記載の方法。
- 前記投与することが、前記対象において発作発生を減らすのに有効な条件下で行われる、請求項14に記載の方法。
- 前記投与することが、前記対象における認知障害を改善するのに有効な条件下で行われる、請求項14に記載の方法。
- 前記投与することが、脳内送達を用いて、髄腔内送達を用いて、鼻腔内送達を用いて、または脳室への直接注入を介して行われる、請求項14に記載の方法。
- 前記対象がヒトである、請求項14に記載の方法。
- 前記REST阻害物質が、グリア細胞を標的とするREST阻害物質である、請求項14に記載の方法。
- 対象において神経精神障害を治療するまたはその発症を抑制する方法であって、
神経精神障害を有するまたはそのリスクを有する対象を選択すること、および
選択された前記対象に、前記対象において前記神経精神障害を治療するのにまたはその発症を抑制するのに有効な条件下でREST阻害物質を投与すること
を含む、前記方法。 - 前記グリア細胞がグリア前駆細胞である、請求項38に記載の方法。
- 前記グリア細胞が星状細胞である、請求項38に記載の方法。
- 前記REST阻害物質がバルプロ酸を含む、請求項38に記載の方法。
- 前記REST阻害物質がベンゾイミダゾール−5−カルボキサミド誘導体を含む、請求項38に記載の方法。
- 前記ベンゾイミダゾール−5−カルボキサミド誘導体が、2−(2−ヒドロキシ−フェニル)−1H−ベンゾイミダゾール−5−カルボン酸アリルオキシ−アミド(X5050)、または2−チオフェン−2−イル−1H−ベンゾイミダゾール−5−カルボン酸(2−エチル−ヘキシル)−アミド(X5917)である、請求項42に記載の方法。
- 前記REST阻害物質がピラゾールプロピオンアミド誘導体を含む、請求項38に記載の方法。
- 前記ピラゾールプロピオンアミド誘導体が、3−[1−(3−ブロモ−フェニル)−3,5−ジメチル−1H−ピラゾール−4−イル]−1−{4−[5−(モルホリン−4−カルボニル)−ピリジン−2−イル]−2−フェニル−ピペラジン−1−イル}−プロパン−1−オン(X38210)、または3−[1−(2,5−ジフルオロ−フェニル)−3,5−ジメチル−1H−ピラゾール−4−イル]−1−{4−[5−(モルホリン−4−カルボニル)−ピリジン−2−イル]−2−フェニル−ピペラジン−1−イル}−プロパン−1−オン(X38207)である、請求項44に記載の方法。
- 前記REST阻害物質が、RESTアンチセンスオリゴヌクレオチド、REST shRNA、REST siRNA、及びREST RNAアプタマーから成る群から選択される阻害性核酸分子を含む、請求項38に記載の方法。
- 前記REST阻害物質が抗REST抗体またはその抗原結合断片を含む、請求項38に記載の方法。
- 前記REST阻害物質が送達ビヒクル中にパッケージされる、請求項38に記載の方法。
- 前記送達ビヒクルがナノ粒子である、請求項48に記載の方法。
- 前記送達ビヒクルが、グリア細胞を標的とする部分を含む、請求項48に記載の方法。
- 前記神経精神障害が、統合失調症、自閉症スペクトラム症、及び双極性障害から成る群から選択される、請求項38に記載の方法。
- 前記神経精神障害が統合失調症である、請求項51に記載の方法。
- 前記投与することが、前記対象においてニューロンの興奮性を減らすのに有効な条件下で行われる、請求項38に記載の方法。
- 前記投与することが、前記対象において発作発生を減らすのに有効な条件下で行われる、請求項38に記載の方法。
- 前記投与することが、前記対象において認知障害を改善するのに有効な条件下で行われる、請求項38に記載の方法。
- 前記投与することが、脳内送達を用いて、髄腔内送達を用いて、鼻腔内送達を用いて、または脳室への直接注入を介して行われる、請求項38に記載の方法。
- 前記対象がヒトである、請求項38に記載の方法。
- 前記REST阻害物質が、グリア細胞を標的とするREST阻害物質である、請求項38に記載の方法。
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US9724432B2 (en) | 2015-04-30 | 2017-08-08 | University Of Rochester | Non-human mammal model of human degenerative disorder, uses thereof, and method of treating human degenerative disorder |
WO2018209022A2 (en) | 2017-05-10 | 2018-11-15 | University Of Rochester | Methods of treating neuropsychiatric disorders |
CN115887655A (zh) * | 2021-09-30 | 2023-04-04 | 中国科学院脑科学与智能技术卓越创新中心 | 直接转分化治疗神经系统疾病 |
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CZ296576B6 (cs) | 1999-02-12 | 2006-04-12 | Sankyo Company Limited | Nukleosidový analog a oligonukleotidový analog a farmaceutický prostredek, sonda a primer s jeho obsahem |
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JP2024075673A (ja) | 2024-06-04 |
WO2019246112A1 (en) | 2019-12-26 |
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