JP2018512841A - 消化管炎症低下および/または消化管粘膜バリア強化の利益を享受する疾患処置のために操作された細菌 - Google Patents
消化管炎症低下および/または消化管粘膜バリア強化の利益を享受する疾患処置のために操作された細菌 Download PDFInfo
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Abstract
Description
本開示は、遺伝学的に操作された細菌、その製薬上組成物、ならびに消化管炎症を減少させ、消化管バリア機能を増強し、および/または自己免疫障害を処置または防止する方法を含む。いくつかの実施態様では、遺伝学的操作細菌には、ノンネイティブな(非自然なとも言う)抗炎症および/または消化管バリア機能エンハンサー分子(群)を生成するための少なくとも一の非自然遺伝子および/または遺伝子カセットが含まれる。少なくとも一の遺伝子および/または遺伝子カセットは、誘発性条件、例は、低酸素環境、ROSの存在、またはRNSの存在を感知することが可能な転写因子によって制御される調節領域にさらに作動可能に連結される。遺伝学的に操作細菌は、誘導性環境、例は、消化管内で抗炎症および/または消化管バリア機能エンハンサー分子(群)を生成することが可能である。したがって、遺伝学的に操作された細菌およびそれらの細菌を含む製薬上組成物は、自己免疫障害および/または消化管炎症および/またはIBDを含む消化管バリア機能低下に関連する疾患または状態を処置または防止するために使用されうる。
細菌
抗炎症および/または消化管バリア機能エンハンサー分子
誘導性調節領域
酸素レベル依存性調節
RNS依存性調節
ROS依存性調節
複数の作用メカニズム
分泌
必須遺伝子および栄養要求体
遺伝学的調節回路
宿主-プラスミド相互依存性
キルスイッチ
変異誘発
製薬上組成物および調剤物
処置の方法
インビボでの処置
参考文献
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Kanaiら、A breakthrough in probiotics: Clostridium butyricum regulates gut homeostasis and anti-inflammatory response in inflammatory bowel disease.(プロバイオティクスでのブレークスルー:クロストリジウム・ブチリカムは、炎症性腸疾患における消化管ホメオスタシスおよび抗炎症応答を調節する。)J Gastroenterol.(ジャーナル・オブ・ガストロエンテロロジー)2015年9月;50(9):928-39。PMID:25940150。
Keatesら、TransKingdom RNA interference: a bacterial approach to challenges in RNAi therapy and delivery.(生物界間のRNA干渉:RNAi療法およびデリバリーにおける課題への細菌的アプローチ。)Biotechnol Genet Eng Rev.(バイオテクノロジー・アンド・ジェネティック・エンジニアリング・レビューズ)2008;25:113-27。PMID:21412352。
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Klemanら、Acetate metabolism by Escherichia coli in high-cell-density fermentation.(高細胞密度発酵におけるエシェリキア・コリによるアセタート代謝。)Appl Environ Microbiol.(アプライド・アンド・エンバイロンメンタル・マイクロバイオロジー)1994年11月;60(11):3952-8。PMID:7993084。
Lernerら、(a) Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease.((a)産業食物添加剤に関連する腸のタイトジャンクション透過性における変化は、自己免疫疾患の発生率の上昇を説明する。)Autoimmun Rev.(オートイムニティ・レビューズ)2015年6月;14(6):479-89。PMID:25676324。
Lernerら、(b) Rheumatoid arthritis-celiac disease relationship: Joints get that gut feeling.((b)リウマチ性関節炎-セリアック病の関係:関節はその消化管の感覚を得る。)Autoimmun Rev.、2015年11月;14(11):1038-47。PMID:26190704。
Low(ロー)ら、Animal models of ulcerative colitis and their application in drug research.(潰瘍性大腸炎の動物モデルおよび薬物研究におけるその応用)Drug Des Devel Ther.(ドラッグ・デザイン、デベロップメント・アンド・セラピー)2013年11月12日;7:1341-57 PMID:24250223。
Lukovacら、Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids.(マウス消化管オルガノイドにおける宿主末梢脂質代謝およびヒストンアセチル化のアッカーマンシア・ムシニフィラおよびフィーカリバクテリウム・プラウスニッツィイによる差次的調節。)MBio.(mBio)2014年8月12日;5(4)。 pii:e01438-14。PMID:25118238。
MacPherson(マクファーソン)BR、Pfeiffer(ファイファー)CJ.、Experimental production of diffuse colitis in rats.(ラットにおけるびまん性大腸炎の実験的生成。)Digestion.(ダイジェスチョン)1978;17(2):135-50。PMID:627326。
Martinezら、Deletion of Mtgr1 sensitizes the colonic epithelium to dextran sodium sulfate-induced colitis.(Mtgr1の欠損は結腸上皮を硫酸デキストラン誘発大腸炎に感作させる。)Gastroenterology。2006年8月;131(2):579-88。PMID:16890610。
Matteoliら、Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction.(消化管CD103+樹状細胞は、T調節/Tエフェクター細胞バランスおよび経口寛容誘導に影響を及ぼすインドールアミン2,3-ジオキシゲナーゼを発現する。)Gut。2010年5月;59(5):595-604。PMID:20427394。
Meadowら、Biosynthesis of diaminopimelic acid and lysine in Escherichia coli.(エシェリキア・コリにおけるジアミノピメリン酸およびリジンの生合成。)Biochem J.(ザ・バイオケミカル・ジャーナル)1959年7月;72(3):396-400。PMID:16748796。
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Mombaerts(モンバーツ)ら、Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice.(T細胞受容体変異マウスにおける炎症性腸疾患の自発的発生。)Cell。1993年10月22;75(2):274-82。PMID:8104709。
Moolenbeek(ムーレンビーク)C、Ruitenberg(ルーテンバーグ)EJ.、The "Swiss roll": a simple technique for histological studies of the rodent intestine.(「スイスロール」:げっ歯類の腸の組織学的研究のための簡単な技術。)Lab Anim.(ラボラトリー・アニマルズ)1981年1月;15(1):57-9。PMID:7022018。
Mooreら、Regulation of FNR dimerization by subunit charge repulsion.(サブユニット電荷反発によるFNR二量化の調節。)J Biol Chem.(ジャーナル・オブ・バイオロジカル・ケミストリー)2006年11月3;281(44):33268-75。PMID:16959764。
Morrisseyら、CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells.(高レベルのCD45RBを発現するCD4+T細胞は、コンジェニックな重症複合免疫不全マウスに移入されるとき、消耗性疾患を誘発する。病気の発症は精製されたCD4+T細胞の共移入によって予防される。)J Exp Med.、1993年7月1;178(1):237-44。PMID:8100269。
Mourelle(ムーレル)ら、Polyunsaturated phosphatidylcholine prevents stricture formation in a rat model of colitis.(多価不飽和ホスファチジルコリンは大腸炎のラットモデルにおける狭窄形成を防止する。)Gastroenterology.、1996年4月;110(4):1093-7。PMID:8612998。
Nguyen(グエン)ら、Lymphocyte-dependent and Th2 cytokine-associated colitis in mice deficient in Wiskott-Aldrich syndrome protein.(ウィスコット・アルドリッチ症候群タンパク質において欠損するマウスにおけるリンパ球依存性およびTh2サイトカイン関連大腸炎。)Gastroenterology、2007年10月;133(4):1188-97。PMID:17764675。
Nielsen。New strategies for treatment of inflammatory bowel disease.(炎症性腸疾患の処置のための新しい戦略。)Front Med (Lausanne).(フロンティアーズ・イン・メディシン(ローザンヌ))2014;1:3。PMID:25685754。
Nougayredeら、Escherichia coli induces DNA double-strand breaks in eukaryotic cells.(エシェリキア・コリは真核細胞においてDNA二本鎖切断を誘導する。)Science。2006年8月11;313(5788):848-51。PMID:16902142。
Ohman(オーマン)ら、Regression of Peyer's patches in G alpha i2 deficient mice prior to colitis is associated with reduced expression of Bcl-2 and increased apoptosis.(結腸炎に先立つGα2欠損マウスにおけるパイエル病のパッチの退行は、Bcl-2の発現の減少およびアポトーシスの増加と関連する。Gut。2002年9月;51(3):392-7。PMID:12171962。
Okayasuら、A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice.(マウスにおける信頼できる実験的に急性な、および慢性潰瘍性大腸炎の誘発における新規な方法。)Gastroenterology。1990年5月;98(3):694-702。PMID:1688816。
Olierら、Genotoxicity of Escherichia coli Nissle 1917 strain cannot be dissociated from its probiotic activity.(エシェリキア・コリ・ニッスル1917株の遺伝毒性はそのプロバイオティクス活性から解離させることはできない。)Gut Microbes.(ガット・マイクローベス。)2012年11月12日;3(6):501-9。PMID:22895085。
Ostanin(オスタニン)ら、T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade.(慢性大腸炎のT細胞移入モデル:そのトレードの概念、考察、およびトリック。)Am J Physiol Gastrointest Liver Physiol.(アメリカン・ジャーナル・オブ・フィジオロジー.ガストロインテスティナル・アンド・リバーフィジオロジー)2009年2月;296(2):G135-46。PMID:19033538。
Paunら、Immuno-ecology: how the microbiome regulates tolerance and autoimmunity.(免疫生態学:微生物がどのように耐性および自己免疫を調節するか。)Curr Opin Immunol.(カレント・オピニオン・イン・イムノロジー)2015年10月10日;37:34-9。PMID:26460968。
Pizarro(ピザロ)ら、SAMP1/YitFc mouse strain: a spontaneous model of Crohn's disease-like ileitis.(SAMP1/YitFcマウス株:クローン病様回腸炎の自然発症モデル。)Inflamm Bowel Dis.。2011年12月;17(12):2566-84。PMID:21557393。
Powrieら、Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice.(表現型的に異なるCD4+T細胞のサブセットは、C.B-17 scid(重症複合免疫不全)マウスにおける慢性腸炎症を誘導または防御する。)Int Immunol.(インターナショナル・イムノロジー)1993年11月;5(11):1461-71。PMID:7903159。
Pugsley。The complete general secretory pathway in gram-negative bacteria.(グラム陰性菌における完全な包括的分泌経路。)Microbiol Rev.(マイクロバイオロジカル・レビューズ)1993年3月;57(1):50-108。PMID:8096622。
Purcellら、Towards a whole-cell modeling approach for synthetic biology.(合成生物学のための全細胞モデル化アプローチに向けて。)Chaos.(カオス)2013年6月;23(2):025112。PMID:23822510。
Ragsdale。Enzymology of the wood-Ljungdahl pathway of acetogenesis.(アセトゲネシス(酢酸生成)のウッド-ユングダール経路の酵素学。)Ann N Y Acad Sci.(アナールズ・オブ・ザ・ニュー・ヨーク・カデミー・オブ・サイエンス)2008年3月;1125:129-36。PMID:18378591。
Rayら、The effects of mutation of the anr gene on the aerobic respiratory chain of Pseudomonas aeruginosa.(シュードモナス・エルジノーサの好気性呼吸鎖に対するanr遺伝子の変異の影響。)FEMS Microbiol Lett.、1997年11月15;156(2):227-32。PMID:9513270。
Reevesら、Engineering Escherichia coli into a protein delivery system for mammalian cells.(哺乳動物細胞のためにエシェリキア・コリのタンパク質デリバリーシステムへの組込み。)ACS Synth Biol.(ACSシンセティック・バイオロジー)2015;4(5):644-54。PMID:25853840。
Reisterら、Complete genome sequence of the Gram-negative probiotic Escherichia coli strain Nissle 1917.(グラム陰性プロバイオティクのエシェリキア・コリ株ニッスル1917の完全なゲノム配列。)J Biotechnol.(ジャーナル・オブ・バイオテクノロジー)2014年10月10日;187:106-7。PMID:25093936。
Rembackenら、Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial.(潰瘍性大腸炎の処置のための非病原性エシェリキア・コリ対メサラジン:無作為化試験。)Lancet(ランセット)1999年8月21;354(9179):635-9。PMID:10466665。
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Rigelら、A new twist on an old pathway - accessory Sec systems.(古い通路での新しいツイスト-アクセサリーSecシステム。)Mol Microbiol.、2008年7月;69(2):291-302。PMID:18544071。
Sabiu(サビウ)ら、Indomethacin-induced gastric ulceration in rats: Ameliorative roles of Spondias mombin and Ficus exasperata.(ラットにおけるインドメタシン誘導胃潰瘍形成:スポンディアス・モンビンおよびフィカス・エグザスペラタの改善的役割)Pharm Biol.(ファーマシューティカル・バイオロジー)2016年1月;54(1):180-6。PMID:25815713。
Saier。Protein secretion and membrane insertion systems in Gram-negative bacteria.(グラム陰性細菌におけるタンパク質分泌および膜挿入システム)J Membr Biol.(ザ・ジャーナル・オブ・メンブレン・バイオロジー)2006;214(2):75-90。PMID:17546510。
Salmonら、Global gene expression profiling in Escherichia coli K12. The effects of oxygen availability and FNR.(エシェリキア・コリK12における全遺伝子発現プロファイリング。酸素利用率およびFNRの効果。)J Biol Chem.、2003年8月8;278(32):29837-55。PMID:12754220。
Sanzら、Microbiota, inflammation and obesity.(微生物叢、炎症および肥満。)Adv Exp Med Biol.(アドバンシーズ・イン)・エクスペリメンタル・メディシン・アンド・バイオロジー)2014;817:291-317。PMID:24997040。
Sanzら、Understanding the role of gut microbiome in metabolic disease risk.(代謝疾患リスクにおける消化管微生物叢の役割の理解。)Pediatr Res.(ペディアトリック・リサーチ)2015年1月;77(1-2):236-44。PMID:25314581。
Satら、The Escherichia coli mazEF suicide module mediates thymineless death.(エシェリキア・コリmazEF自殺モジュールはチミンレス死を媒介する。)J Bacteriol.、2003年3月;185(6):1803-7。PMID:12618443。
Satoh(サトー)ら、 New ulcerative colitis model induced by sulfhydryl blockers in rats and the effects of antiinflammatory drugs on the colitis.(ラットにおけるスルフヒドリル遮断薬によって誘導される新規潰瘍性大腸炎モデルおよび大腸炎に対する抗炎症薬の効果)Jpn J Pharmacol.(ジャパニーズ・ジャーナル・オブ・ファーマコロジー)1997年4月;73(4):299-309。PMID:9165366。
Sawers。Identification and molecular characterization of a transcriptional regulator from Pseudomonas aeruginosa PAO1 exhibiting structural and functional similarity to the FNR protein of Escherichia coli.(エシェリキア・コリのFNRタンパク質と構造的および機能的類似性を示すシュードモナス・エルジノーサPAO1の転写調節因子の同定および分子特性。)Mol Microbiol.、1991年6月;5(6):1469-81。PMID:1787797。
Schiel-Bengelsdorfら、Pathway engineering and synthetic biology using acetogens.(アセトゲンを用いる経路工学および合成生物学。)FEBS Lett.、2012年7月16;586(15):2191-8。PMID:22710156。
Schultz。Clinical use of E. coli Nissle 1917 in inflammatory bowel disease.(炎症性腸疾患におけるE. coliニッスル1917の臨床的使用。)Inflamm Bowel Dis.。2008年7月;14(7):1012-8。Review(レビュー)。PMID:18240278。
Segui(セグイ)ら、Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine.(スーパーオキシドジスムターゼは、炎症腸への酸化ストレス、接着分子発現、および白血球動員を減少させることによってTNBS誘発性大腸炎を改善する。)J Leukoc Biol.(ジャーナル・オブ・ロイコサイト・バイオロジー)2004年9月;76(3):537-44。PMID:15197232。
Selmerら、Propionate CoA-transferase from Clostridium propionicum. Cloning of gene and identification of glutamate 324 at the active site.(クロストリジウム・プロピオニカムからのプロピオナートCoAトランスフェラーゼ。活性部位におけるグルタマート324の遺伝子のクローニングおよび同定。Eur J Biochem.、2002年1月;269(1):372-80。PMID:11784332。
Simpsonら、IBD: microbiota manipulation through diet and modified bacteria.(IBD:食餌および改変細菌を通した微生物の操作。)Dig Dis.(ダイジェスティブ・ディジーズ)2014;32 Suppl(付録)1:18-25。PMID:25531349。
Smithら、The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.(微生物代謝物、短鎖脂肪酸は、結腸Treg細胞ホメオスタシスを調節する。)Science。2013年8月2;341(6145):569-73。PMID:23828891。
Sonnenbornら、The non-pathogenic Escherichia coli strain Nissle 1917 - features of a versatile probiotic.(非病原性エシェリキア・コリ株ニッスル1917−汎用性のあるプロバイオティクスの特徴。)Microbial Ecology in Health and Disease(マイクロバイアル・エコロジー・イン・ヘルス・アンド・ディジーズ)。2009;21:122-58。
Stanleyら、Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system.(マイコバクテリウム・ツベルクローシスによる急性感染症およびマクロファージ破壊は特殊な分泌系を必要とする。)Proc Natl Acad Sci USA。2003年10月;100(22):13001-6。PMID:14557536。
Sugimoto(スギモト)ら、IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis.(IL-22は、潰瘍性大腸炎のマウスモデルにおける腸炎症を改善する。)J Clin Invest.(ザ・ジャーナル・オブ・クリニカル・インベスティゲーション)2008年2月;118(2):534-44。PMID:18172556。
Triantafillidisら、Current and emerging drugs for the treatment of inflammatory bowel disease.(炎症性腸疾患の治療のための現在および新興の薬物。)Drug Des Devel Ther 5.5(2011):185-210。
Trunkら、Anaerobic adaptation in Pseudomonas aeruginosa: definition of the Anr and Dnr regulons.(シュードモナス・エルジノーサにおける嫌気的適応:AnrおよびDnrレギュロンの定義。)Environ Microbiol.(エンバイロンメンタル・マイクロバイオロジー)2010年6月;12(6):1719-33。PMID:20553552。
Tsengら、Controlled biosynthesis of odd-chain fuels and chemicals via engineered modular metabolic pathways.(操作されたモジュール式代謝経路を介する奇数鎖の燃料および化学物質の制御された生合成。)Proc Natl Acad Sci USA A. 2012年10月30;109(44):17925-30。PMID:23071297。
Turskiら、Kynurenic Acid in the digestive system-new facts, new challenges.(消化器系でのキヌレニック酸-新しい事実、新たな挑戦。)Int J Tryptophan Res.(インターナショナル・ジャーナル・オブ・トリプトファン・リサーチ)2013年9月4日;6:47-55。PMID:24049450。
Ukenaら、Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity.(プロバイオティックのエシェリキア・コリのニッスル1917は、粘膜の完全性を増強することによって漏出性の腸を抑制する。)PLoS One。2007年12月12日;2(12):e1308。PMID:18074031。
Undenら、Alternative respiratory pathways of Escherichia coli: energetics and transcriptional regulation in response to electron acceptors.(エシェリキア・コリの代替呼吸経路:電子受容体に応答するエネルギー論および転写調節。)Biochim Biophys Acta.(バイオキミカ・エト・バイオフィジカ・アクタ)1997年7月4日;1320(3):217-34。PMID:9230919。
Vargaら、N-Methyl-D-aspartate receptor antagonism decreases motility and inflammatory activation in the early phase of acute experimental colitis in the rat.(N-メチル-D-アスパラギン酸受容体アンタゴニズムは、ラットにおける急性実験的大腸炎の初期段階での運動性および炎症活性を低下させる。)Neurogastroenterol Motil.(ニューロガストロエンテロロジー・アンド・モーティリティ)2010年2月;22(2):217-25。PMID:19735360。
Wagner(ワーグナー)ら、Semisynthetic diet ameliorates Crohn's disease-like ileitis in TNFΔARE/WT mice through antigen-independent mechanisms of gluten.(半合成餌料は、グルテンの抗原非依存性機構を介してTNFΔARE/ WTマウスにおけるクローン病様回腸炎を改善する。)Inflamm Bowel Dis.、2013年5月;19(6):1285-94。PMID:23567784。
Watanabe(ワタナベ)ら、Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa.(インターロイキン7トランスジェニックマウスは、結腸粘膜におけるインターロイキン7タンパク質蓄積の減少を伴う慢性大腸炎を発症する。)J Exp Med.、1998年2月2日;187(3):389-402。PMID:9449719。
Weiら、Mesenteric B cells centrally inhibit CD4+ T cell colitis through interaction with regulatory T cell subsets.(腸間膜B細胞は調節性T細胞サブセットとの相互作用を介してCD4+ T細胞大腸炎を一元的に抑制する。)Proc Natl Acad Sci USA。2005年2月8;102(6):2010-15。PMID:15684084。
Wenら、Innate immunity and intestinal microbiota in the development of Type 1 diabetes.(1型糖尿病の発症における先天性免疫および腸内微生物叢。)Nature。2008 Oct 23;455(7216):1109-13。PMID:18806780。
Whittemら、Murine colitis modeling using dextran sulfate sodium (DSS).(デキストラン硫酸ナトリウム(DSS)を用いるマウス大腸炎モデル。)J Vis Exp.(ジャーナル・オブ・ビジュアライズド・エクスペリメンツ)2010 Jan 19;(35)。PMID:20087313。
Wilk(ウィルク)ら、The mdr1a-/- mouse model of spontaneous colitis: a relevant and appropriate animal model to study inflammatory bowel disease.(自然発症大腸炎のmdr1a -/-マウスモデル:炎症性腸疾患を研究するための関連し、および適切な動物モデル。)Immunol Res.(イムノロジック・リサーチ)2005;31(2):151-9。PMID:15778512。
Williams(ウィリアムズ)GT、Williams WJ.、Granulomatous inflammation--a review.(肉芽腫性炎症-レビュー。)J Clin Pathol.(ジャーナル・オブ・クリニカル・パソロジー)1983 Jul;36(7):723-733。PMID:6345591。
Wintelerら、The homologous regulators ANR of Pseudomonas aeruginosa and FNR of Escherichia coli have overlapping but distinct specificities for anaerobically inducible promoters. Microbiology.(シュードモナス・エルジノーサの相同調節因子ANRおよびエシェリキア・コリのFNRは嫌気的誘導性プロモーターに対して重複しているが明確な特異性を有する。)Microbiology(マイクロバイオロジー)1996 Mar;142(Pt 3):685-93。PMID:8868444。
Wolfら、Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease.(ヒト炎症性腸疾患におけるインドールアミン2,3-ジオキシゲナーゼの過剰発現。)Clin Immunol.(クリニカル・イムノロジー)2004 Oct;113(1):47-55。PMID:15380529。
Wrightら、GeneGuard: A Modular Plasmid System Designed for Biosafety.(ジーンガード:バイオセーフティのために設計されたモジュール式プラスミドシステム。)ACS Synth Biol.、2015年3月20日;4(3):307-16。PMID:24847673。
Xiaoら、Nanoparticles with surface antibody against CD98 and carrying CD98 small interfering RNA reduce colitis in mice.(CD98に対する表面抗体およびCD98低分子干渉RNAを有するナノ粒子は、マウスにおいて大腸炎を減少させる。)Gastroenterology。2014 May;146(5):1289-300。PMID:24503126。
Yazbeckら、Growth factor based therapies and intestinal disease: is glucagon-like peptide-2 the new way forward?(成長因子ベースの治療法および腸疾患:グルカゴン様ペプチド-2は新しい方法か?)Cytokine Growth Factor Rev.(サイトカイン・アンド・グロース・ファクター・レビューズ)2009 Apr;20(2):175-84。PMID:19324585。
Zhangら、Deletion of interleukin-6 in mice with the dominant negative form of transforming growth factor beta receptor II improves colitis but exacerbates autoimmune cholangitis.(ドミナントネガティブ型のトランスフォーミング増殖因子β受容体IIを有するマウスにおけるインターロイキン-6の欠損は、大腸炎を改善するが、自己免疫性胆管炎を悪化させる。)Hepatology。2010 Jul;52(1):215-22。PMID:20578264。
Zimmermannら、Anaerobic growth and cyanide synthesis of Pseudomonas aeruginosa depend on anr, a regulatory gene homologous with fnr of Escherichia coli.(シュードモナス・エルジノーサの嫌気的増殖およびシアン化物合成は、エシェリキア・コリのfnrと相同な調節遺伝子anrに依存する。)Mol Microbiol.、1991 Jun;5(6):1483-90。PMID:1787798。
例
例1.治療上の分子を生成するためのベクターの構築
ブチラート
第3のブチラート遺伝子カセットにおいて、pbtおよびbuk遺伝子はtesB(配列番号10)で置換される。TesBはブチリル-coAからブチラートを開裂させ、そのようにpbt-bukの必要性を排除するE.coliに見出されるチオエステラーゼである(図2参照)。
一定の構築物では、上記のブチラート(酪酸とも言う)産生経路に加えて、E. coli(エシェリキア・コリ、大腸菌とも言う)Nissleは、IL-10、IL-2、IL-22、IL-27、SOD、キヌレニン(kyurenine、キュレニンとも言う)、キヌレン酸(kyurenic acid、キュレイク酸とも言う)、およびGLP-2を生産するために、上記の方法を用いてさらに操作される。いくらかの実施態様では、本細菌は、上記のようなブチラートを産生するための遺伝子カセット、およびIL-10をコードする遺伝子(例は、配列番号49参照)を含む。いくらかの実施態様において、本細菌は、上記のようにブチラートを産生するための遺伝子カセット、およびIL-2をコードする遺伝子を含む(例は、50参照)。いくらかの実施態様において、本細菌は、上記のようにブチラートを産生するための遺伝子カセット、およびIL-22をコードする遺伝子を含む(例は、51参照)。いくらかの実施態様では、本細菌は、上記のようにブチラートを産生するための遺伝子カセット、およびIL-27をコードする遺伝子を含む(例は、配列番号52参照)。いくらかの実施態様では、本細菌は、上記のようにブチラートを産生するための遺伝子カセット、およびSODをコードする遺伝子を含む(例は、53参照)。いくらかの実施態様では、本細菌は、上記のようにブチラートを産生するための遺伝子カセット、およびGLP-2をコードする遺伝子を含む(例は、配列番号54参照)。いくらかの実施態様では、本細菌は、上記のようにブチラートを産生するための遺伝子カセット、およびキュレニンまたはキュウリン酸を産生するための遺伝子または遺伝子カセットを含む。いくらかの実施態様では、本細菌は、上記のようにブチラートを産生するための遺伝子カセット、およびIL-10、IL-22、およびGLP-2をコードする遺伝子を含む。一実施態様では、各々の遺伝子または遺伝子カセットは、配列番号55-66(表9)から選択されるFNR調節領域の制御下に置かれる。代替の実施態様では、遺伝子または遺伝子カセットのそれぞれは、RNS応答性調節領域、例は、norBの制御下に置かれ、および本細菌は、対応するRNS応答性転写因子、例は、nsrRをコードする遺伝子をさらに含む(例は、表10および11参照)。さらに別の実施態様において、遺伝子または遺伝子カセットのそれぞれは、ROS応答性調節領域、例は、oxySの制御下に置かれ、および本細菌は、対応するROS応答性転写因子、例は、oxyRをコードする遺伝子をさらに含む(例は、表14-17参照)。一定の構築物では、1以上の遺伝子をテトラサイクリン誘導性または構成的プロモーターの制御下に置く。
ブチラート、プロピオナート、IL-10、IL-22、IL-2、IL-27
ブチラート、プロピオナート、IL-10、L-22、SOD、GLP-2、キヌレニン
ブチラート、プロピオナート、IL-10、IL-27、IL-22、IL-2、SOD、GLP-2、キヌレニン
「Oligonucleotide」→「オリゴヌクレオチド」
「Cell wall」→「細胞壁」
各プラスミドをE. coli(大腸菌)NissleまたはE. coli DH5aに形質転換する。すべての試験管、溶液、およびキュベットは4℃まで予備チルド冷却する。E. coli NissleまたはE.coli DH5aの一昼夜培養物を5mLの溶原性ブロス(LB)において1:100に希釈し、およびそれが0.4-0.6のOD600に達するまで増殖させる。細胞培養培地は、選択マーカー、例は、プラスミドに適するアンピシリンを含む。次いでE. coli細胞を2,000rpmにて5分間4℃で遠心分離し、上清を除去し、および細胞を1mLの4℃の水に再懸濁する。E. coliを再び2,000rpmにて5分間4℃で遠心分離し、上清を除去し、および細胞を0.5mLの4℃の水に再懸濁する。E. coliを再び2,000rpmにて5分間4℃で遠心分離し、上清を除去し、および最後に細胞を0.1mLの4℃の水に再懸濁する。エレクトロポレーターは2.5kVに設定される。0.5μgの上記プラスミドの1つを細胞に添加し、ピペットによって混合し、およびピペットにより、滅菌してあるチルド冷却したキュベットに入れる。乾燥したキュベットをサンプルチャンバーに入れ、および電気パルスを適用する。室温でのSOC培地1mLを直ちに加え、および混合物を培養管に移し、そして37℃で1時間インキュベートする。細胞は、アンピシリンを含有するLBプレート上に広げ、および一昼夜インキュベートする。
例3.tet誘導性プロモーターを用いる組換えE. coliにおけるブチラートの生産
ブチラートの生成に対する酸素の影響を決定するために、ブチラートの生成を上記のブチラートカセットを含むE. coliのNissle株で評価する。すべてのインキュベーションを37℃で行う。ブチラートカセットで形質転換されたE.coli株DH5aおよびNissleの培養物をLB中で一晩増殖させ、および次いで0.5%グルコースを含む4mLのM9最小培地に1:200に希釈する。細胞を振盪(250rpm)しながら4-6時間増殖させ、およびCoy嫌気性(Coy anaerobic)チャンバー(90%N2、5%CO2、5%H2を供給する)中で好気的または嫌気的にインキュベートする。1mLの培養アリコートを、1.5mLのキャップ付き試験管中で調製し、および定常インキュベーター(stationary incubator)内でインキュベートして培養通気を制限する。1つの試験管を各時点(0、1、2、4、および20時間)に取り出し、およびLC-MSによってブチラート濃度を分析して、これらの組換え株におけるブチラート産生が低酸素環境下で達成できることを確認する。
例5.IBDのマウスモデルにおけるブチラート発現細菌の有効性
例6.IBDのDSS誘導マウスモデルの作製
例7.インビボでの疾患進行のモニタリング
例8. DSS誘導後の遺伝学的に操作された細菌のインビボ有効性
例9.IBDのげっ歯類モデルの安楽死手順
例10.結腸組織の分離および保存
例11.ミエロペルオキシダーゼ活性アッセイ
例12.RNA分離および遺伝子発現分析
例13.組織学
例14.げっ歯類の結腸のエクスビボ培養
例15.TNBS誘発後の遺伝学的に操作された細菌のインビボ有効性
例16.IBDの細胞移入マウスモデルの作製
CD4 T細胞についての豊富化
CD4+ T細胞の蛍光標識
CD4+CD45RBHi T細胞の精製
養子移入
例17.CD45RBHi T細胞トランスファーモデルにおける遺伝学的に操作された細菌の有効性
例18.遺伝学的マウスモデルのIBDにおける遺伝学的に操作された細菌の有効性
例19.IBDのトランスジェニックラットモデルにおける遺伝学的操作細菌の有効性
例19.ブチラート生成細菌株は低用量DSS誘導マウスモデルのIBDにおいて消化管炎症を減少させる
例20:一酸化窒素誘導性レポーター構築物
Claims (25)
- a)外因性環境条件によって誘導され、以下の:
i.ノンネイティブな抗炎症分子をコードする第一の遺伝子;
ii.ノンネイティブな消化管バリア機能エンハンサー分子をコードする第一の遺伝子;および
iii.生合成経路をコードする遺伝子カセットであり、生合成経路の最終生成物は抗炎症分子および消化管バリア機能エンハンサー分子からなる群より選ばれるもの
の一以上に作動可能に連結される第一のプロモーター
を含む、遺伝学的に操作された細菌。 - 第一のプロモーターは低酸素または嫌気条件下で誘導される、請求項1の細菌。
- 低酸素または嫌気条件下で誘導される第一のプロモーターは、FNR応答性プロモーター、ANR応答性プロモーター、またはDNR応答性プロモーターである、請求項2の細菌。
- 第一のプロモーターはFNR応答性プロモーターである、請求項3の細菌。
- 第一のプロモーターは反応性窒素種の存在によって誘導される、請求項1の細菌。
- 第一のプロモーターは反応性酸素種の存在によって誘導される、請求項1の細菌。
- 第一の遺伝子および/または遺伝子カセットは細菌の染色体上に位置する、請求項1-6のいずれか一項の細菌。
- 第一の遺伝子および/または遺伝子カセットは細菌のプラスミド上に位置する、請求項1-7のいずれか一項の細菌。
- 抗炎症および/または消化管バリアエンハンサー分子は、短鎖脂肪酸、プロピオナート、ブチラート、アセタート、IL-10、IL-27、TGF-β2、TGF-β1、GLP-2、NAPEs、エラフィン、およびトレフォイル因子から選ばれる、請求項1-8のいずれか一項の細菌。
- 抗炎症および/または消化管バリアエンハンサー分子は、TNF-α、IFN-γ、IL-1β、IL-6、IL-8、IL-17、CXCL-8、およびCCL2から選ばれる炎症促進性分子に対して向けられるscFv、アンチセンスRNA、siRNA、およびshRNAから選ばれる、請求項1-8のいずれか一項の細菌。
- 細菌はプロバイオティク細菌である、請求項1-10のいずれか一項の細菌。
- 細菌は、バクテロイデス属、ビフィドバクテリウム属、クロストリジウム属、エシェリキア属、ラクトバチルス属、およびラクトコッカス属からなる群より選ばれる、請求項11の細菌。
- 細菌は、エシェリキア・コリ株ニッスルである、請求項12の細菌。
- 細菌は、哺乳動物の消化管内に存在するとき補完される遺伝子において栄養要求体である、請求項1-13のいずれか一項の細菌。
- 哺乳動物の消化管はヒト消化管である、請求項14の細菌。
- 細菌は、ジアミノピメリン酸、またはチミン生合成経路における酵素において栄養要求体である、請求項14または15の細菌。
- 細菌は、細菌に対し毒性がある物質をコードする第二の遺伝子を所有するようにさらに操作され、第二の遺伝子は、哺乳動物の消化管において自然に存在しない環境因子によって、直接的または間接的に誘導される第二のプロモーターの制御下にある、請求項1-16のいずれか一項の細菌。
- 細菌は、細菌に対し毒性がある物質をコードする第三の遺伝子を所有するようにさらに操作され、第三の遺伝子は第一のプロモーターの制御下にあり、および毒性物質の発現は、抗炎症分子、消化管バリアエンハンサー分子、または生合成経路をコードする遺伝子カセットの発現と比較して時間的に遅れる、請求項1-17のいずれか一項の細菌。
- 請求項1-18のいずれか一項の細菌;および薬学的に許容可能な担体を含む、薬学的に許容可能な組成物。
- 経口または直腸施与用に調剤される、請求項19の組成物。
- 自己免疫障害を処置または防止するにあたり、その必要があるペイシェントに、請求項19または20のいずれか一項の組成物を施与するステップを含む、方法。
- 消化管炎症および/またはの低下した消化管バリア機能に関連する疾患または状態を処置するにあたり、請求項19または20のいずれか一項の組成物をその必要があるペイシェントに施与するステップを含む、方法。
- 自己免疫障害は、急性散在性脳脊髄炎(ADEM)、急性壊死性出血性白質脳炎、アジソン病、無ガンマグロブリン血症、円形脱毛症、アミロイドーシス、強直性脊椎炎、抗GBM/抗TBM腎炎、抗リン脂質症候群(APS)、自己免疫性血管性浮腫、自己免疫性再生不良性貧血、自己免疫性自律神経障害、自己免疫性溶血性貧血、自己免疫性肝炎、自己免疫性高脂血症、自己免疫性免疫不全、自己免疫性内耳疾患(AIED)、自己免疫性心筋炎、自己免疫性卵巣炎、自己免疫性膵炎、自己免疫性網膜症、自己免疫性血小板減少性紫斑病(ATP)、自己免疫性甲状腺疾患、自己免疫性蕁麻疹、軸索アンド神経ニューロパシー、バロー病、ベーチェット病、水疱性類天疱瘡、心筋ミオパチー、キャッスルマン病、セリアック病、シャーガス病、慢性炎症性脱髄性多発ニューロパチー(CIDP)、慢性再発性多発性骨髄炎(CRMO)、チャーグ・ストラウス症候群、瘢痕性類天疱瘡/良性粘膜類天疱瘡、クローン病、コーガン症候群、寒冷凝集素症、先天性心ブロック、コクサッキー心筋炎、CREST疾患、本態性混合性クリオグロブリン血症、脱髄性ニューロパチー、疱疹状皮膚炎、皮膚筋炎、デビック病(視神経脊髄炎)、円板状ループス、ドレスラー症候群、子宮内膜症、好酸球性食道炎、好酸球性筋膜炎、結節性紅斑、実験的アレルギー性脳脊髄炎、エヴァンズ症候群、線維性肺胞炎、巨細胞性動脈炎(側頭動脈炎)、巨細胞性心筋炎、糸球体腎炎、グッドパスチャー症候群、多発血管炎性肉芽腫症(GPA)、グレーヴス病、ギラン・バレー症候群、ハシモト脳炎、ハシモト甲状腺炎、溶血性貧血、ヘノッホ・シェーンライン紫斑病、妊娠性疱疹、低ガンマグロブリン血、特発性血小板減少性紫斑病(ITP)、IgA腎症、IgG4関連硬化性疾患、免疫調節性リポタンパク質、封入体筋炎、間質性膀胱炎、若年性関節炎、若年性特発性関節炎、若年性筋炎、カワサキ症候群、ランバート・イートン症候群、白血球破砕性血管炎、扁平苔癬、硬化性苔癬、木質性結膜炎、線状IgA病(LAD)、ループス(全身性エリトマトーデス)、慢性ライム病、メニエール病、顕微鏡的多発血管炎、混合性結合組織病(MCTD)、モーレン潰瘍、ムッハ・ハーベルマン病、多発性硬化症、重症筋無力症、筋炎、ナルコレプシー、視神経脊髄炎(デビック)、好中球減少症、眼瘢痕性類天疱瘡、視神経炎、パリンドロームリウマチ、PANDAS(連鎖球菌に関連する小児自己免疫神経精神障害)、腫瘍随伴性小脳変性症、発作性夜間ヘモグロビン尿症(PNH)、パリーロンベルグ症候群、パーソンネージターナー症候群、扁平部炎(周辺部ぶどう膜炎)、天疱瘡、末梢性ニューロパチー、静脈周囲脳脊髄炎、悪性貧血、POEMS症候群、結節性多発動脈炎、I型、II型およびIII型自己免疫性多腺性症候群、リウマチ性多発筋痛、多発性筋炎、心筋梗塞後症候群、心膜切開後症候群、プロゲステロン皮膚炎、原発性胆汁性肝硬変、原発性硬化性胆管炎、乾癬、乾癬性関節炎、特発性肺線維症、壊疽性膿皮症、赤芽球癆、レイノー現象、反応性関節炎、反射性交感神経性ジストロフィー、ライター症候群、再発性多発軟骨炎、下肢静止不能症候群、後腹膜線維症、リウマチ熱、関節リウマチ、サルコイドーシス、シュミット症候群、強膜炎、強皮症、シェーグレン症候群、精子および精巣の自己免疫、スティフパーソン症候群、亜急性細菌性心内膜炎(SBE)、スザック症候群、交感性眼炎、タカヤス動脈炎、側頭動脈炎/巨細胞性動脈炎、血小板減少性紫斑病(TTP)、トロサ・ハント症候群、横断性脊髄炎、1型糖尿病、喘息、潰瘍性大腸炎、未分化結合組織病(UCTD)、ぶどう膜炎、脈管炎、小水疱性外皮疾患、白斑、およびウエゲナー肉芽腫症からなる群より選ばれる、請求項21の方法。
- 自己免疫障害は、1型糖尿病、ループス、関節リウマチ、潰瘍性大腸炎、若年性関節炎、乾癬、乾癬性関節炎、セリアック病、および強直性脊椎炎からなる群より選ばれる、請求項23の方法。
- 疾患または状態は、クローン病および潰瘍性大腸炎を含む炎症性腸疾患、および下痢性疾患から選ばれる、請求項22の方法。
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