JP2023523214A - 血管作動性腸ペプチドを発現する微生物、及びその用途 - Google Patents
血管作動性腸ペプチドを発現する微生物、及びその用途 Download PDFInfo
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- JP2023523214A JP2023523214A JP2022563907A JP2022563907A JP2023523214A JP 2023523214 A JP2023523214 A JP 2023523214A JP 2022563907 A JP2022563907 A JP 2022563907A JP 2022563907 A JP2022563907 A JP 2022563907A JP 2023523214 A JP2023523214 A JP 2023523214A
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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Abstract
Description
(i)ステロイド性抗炎症剤
dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, predonisolone, methylpredonisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone dipropionate, estriol, paramethasone acetate, fludrocortisone acetate, clobetasol propionate, diflorasone acetate, dexamethasone propionate, difluprednate, betamethasone dipropionate, budesonide, diflucortolone valerate, amcinonide, halcinonide, mometasone furoate, hydrocortisone butyrate propionate, flumetasone pivalate, clobetasone butyrate, dexametasone acetateなど
(ii)5-アミノサリチル酸
sulfasalazine, mesalazine, olsalazine, balsalazideなど
(iii)免疫調節剤(immunomodulator)または免疫抑制剤(immunosuppressant)
methotrexate, cyclophosphamide, MX-68, atiprimod dihydrochloride, BMS-188667, CKD-461, rimexolone, cyclosporine, tacrolimus, gusperimus, azathiopurine, antilymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferonなど
(iv)JAK阻害剤
tofacitinib, ruxolitinibなど
(v)TNF阻害剤
組み換えTNF-アルファ-受容体IgG-Fc融合タンパク質(etanercept)、infliximab, adalimumab, certolizumab pegol, golimumab, PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF-α antibody, CDP571など
(vi)インテグリン阻害剤
natalizumab, vedolizumab, AJM300, TRK-170, E-6007など
(vii)インターロイキン-12/23阻害剤
ustekinumab, briakinumab (anti-interleukin-12/23 antibody)など
(viii)非ステロイド性抗炎症剤(NSAID)
(a)古典的NSAID
alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam, nabumeton, acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, ketophenylbutazone, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, piroxicam, tenoxicam, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, bucolome, benzbromarone, allopurinol, sodium aurothiomalate, hyaluronate sodium, sodium salicylate, salicylic acid, atropine, scopolamine, levorphanol, oxymorphone、またはその塩など
(b)シクロオキシゲナーゼ阻害剤(COX-1選択的阻害剤、COX-2選択的阻害剤など)
サリチル酸誘導体(例:celecoxib, aspirin), etoricoxib, valdecoxib, diclofenac sodium, indomethacin, loxoprofenなど
(c)ニトリックオサイド放出NSAID(nitric oxide-releasing NSAID)。
前記微生物に係わる記載事項は、前記組成物についても、適用可能である。
Lactobacillus brevis LMT1-46(KCTC 13423BP)を利用し、乳酸菌で一般的に使用される相同組み換え遺伝子操作方法(Zhang et al., D-Ala-D-Ala ligase as a broad host-range counterselection marker in vancomycin resistant lactic acid bacteria, J. Bacteriol., 2018)により、外来VIPを発現する組み換え微生物を作製した。
組み換え微生物が意図されているように生成されたか否かということを確認するために、PCRを進めた。MRSプレートにおいて37℃、16時間静置培養された乳酸菌コロニーを使用した。蒸溜水100μlが込められたチューブに、シングルコロニーをピーキングして懸濁させた。それをビードビーティング(bead-beating)した後、98℃で10分間加熱し、DNAテンプレートとして使用した。DNAテンプレート1μl、正方向プライマー1μl、逆方向プライマー1μl、DNA重合酵素ミックス25μlを混ぜ、PCR用混合液を作った。PCR条件は1、サイクル当たり(a)変性段階、98℃で10秒、(b)アニーリング段階、55℃で15秒、及び(c)延長段階、72℃で10秒で構成された40サイクルの増幅段階、並びに72℃で2分で構成された最終延長段階で実施した。使用プライマーは、操作する遺伝子部位のORF外領域にデザインされ、配列は、下記表1に記述されている。
組み換え微生物のVIP生産性が向上されたか否かということを確認するために、実施例1で作製された菌株のVIP発現量確認のための評価を進めた。作製された菌株のスタックをMRSプレートにストリーキングし、37℃で3日間静置培養した。そこから、シングルコロニーを選び、MRS液体培地において、37℃、24時間振盪培養した。それを、25ml MRSに、OD600が0.1になるように接種した後、37℃で16時間振盪培養した。菌株培養液10mlを抽出し、4,000rpm、10分間遠心分離し、上澄み液のみを抽出し、TCA(tricholoacetic acid)を1ml添加し、4℃で30分以上処理した。それを、10,000rpmで10分間遠心分離し、上澄み液を除去した後、4℃に保管されたアセトン1mlを利用し、ペレットを懸濁させた。13,000rpmで10分間遠心分離し、上澄み液を除去した後、アセトン0.5mlを添加し、ペレットを懸濁させた。それを、再び13,000rpmで10分間遠心分離し、60℃で5分間乾燥させる過程を経た。サンプルバッファ(還元バッファ)を添加し、ペレットを十分に混ぜ、98℃で10分間処理した。それを利用し、ウェスタンブロッティングを進めた。該ウェスタンブロッティングの結果を基に、ImageJというプログラムを利用し、同一サイズの領域によって測定されるバンドの強度を定量化した。
栄養要求株が、意図されているように生成されたか否かということを確認するために、PCRを進めた。MRSプレートにおいて37℃、16時間静置培養された乳酸菌コロニーを使用した。蒸溜水100μlが込められたチューブに、シングルコロニーをピッキングして懸濁させた。それをビードビティングした後、98℃で10分間加熱し、DNAテンプレートとして使用した。DNAテンプレート1μl、正方向プライマー1μl、逆方向プライマー1μl、DNA重合酵素ミックス25μlを混ぜ、PCR用混合液を作った。PCR条件は、1サイクル当たり(a)変性段階、98℃で10秒、(b)アニーリング段階、55℃で15秒、及び(c)延長段階、72℃で10秒で構成された40サイクルの増幅段階、並びに72℃で2分で構成された最終延長段階で実施した。使用プライマーは、操作する遺伝子部位のORF内側及びORF外側領域にデザインされ、配列は、下記下表2に記述されている。
実施例1で作製された菌株の生長パターンを知るために、生長試験を進めた。作製された菌株のスタックをMRSプレートにストリーキングし、37℃で3日間静置培養した。そこから、シングルコロニーを選び、MRS液体培地において、37℃、24時間振盪培養した(230rpm)。培養液1mlを抽出し、13,000rpmで1分間遠心分離した。1x PBS溶液1mlで細胞ペレットを懸濁させた後、OD600を測定し、生長が阻害されうる環境であるSDM(semi-defined media)という乳酸菌用最小培地25mlに、OD600が0.0025になるように接種した。37℃における振盪培養(230rpm)条件で40時間培養し、接種後、15,17,20,22,24,40時間の時点において、OD600を測定した値をグラフに示した。
形質転換菌株由来VIPタンパク質治療効能を評価するために、形質転換菌株をDSS(dextransulfate sodium)で誘導されたマウス腸炎症モデルに経口投与した後、生存率またはDAI(disease activity index)点数を確認した。5mlのMRS培地において一日一次培養した後、培養した菌株を、50mlのMRS培地に、OD600が0.1になるように接種した。16~18時間後、培養液のOD600が4~5になれば、総投与マウス個体数と給与回数とに合わせて菌株を回収した。4,000rpmで10分間遠心分離し、培養上澄み液を除去して回収された菌株は、匹当たり1回1x109cfuで投与するように、1x PBSに浮遊させた。菌株投与は、1日1回、総16日間施された。
[受託番号]
寄託機関:韓国生命工学研究院
受託番号:KCTC 13421BP
受託日:20171212
寄託機関:韓国生命工学研究院
受託番号:KCTC 13422BP
受託日:20171212
寄託機関:韓国生命工学研究院
受託番号:KCTC 13423BP
受託日:20171212
国際的承認に係わるブダペスト条約
国際的様式
To.メディトックス株式会社
メディトックス株式会社
大韓民国京畿道水原市霊通区セントラルタウン路114
16506
下記国際寄託機関により、規則7.1に依拠して発行された寄託証原本
様式BP/4(KCTC form17)
国際的承認に係わるブダペスト条約
国際的様式
To.メディトックス株式会社
メディトックス株式会社
大韓民国京畿道水原市霊通区セントラルタウン路114
16506
下記国際寄託機関により、規則7.1に依拠して発行された寄託証原本
様式BP/4(KCTCform17)
Claims (15)
- プロモーター、及び前記プロモーターと作動可能に連結された血管作動性腸ペプチド(VIP)をコーディングする外来遺伝子が導入され、プロテアーゼが不活性化されている組み換え微生物であり、ラクトバシラス(Lactobacillus)属である、組み換え微生物。
- ラクトバチルス・パラカゼイ(Lactobacillus paracasei)、ラクトバチルス・ブレビス(Lactobacillus brevis)またはラクトバチルス・プランタルム(Lactobacillus plantarum)である、請求項1に記載の微生物。
- 構成的プロモーター(constitutive promoter)、及び前記プロモーターと作動可能に連結された血管作動性腸ペプチド(VIP)をコーディングする外来遺伝子が導入されプロテアーゼが不活性化されている組み換え微生物であり、乳酸菌である、組み換え微生物。
- 前記乳酸菌は、ラクトバシラス(Lactobacillus)属、またはラクトコッカス(Lactococcus)属である、請求項3に記載の微生物。
- 前記乳酸菌は、ラクトバチルス・パラカゼイ(Lactobacillus paracasei)、ラクトバチルス・ブレビス(Lactobacillus brevis)、ラクトバチルス・プランタルム(Lactobacillus plantarum)またはラクトコッカス・ラクチス(Lactococcus lactis)である、請求項4に記載の微生物。
- 前記プロモーターと前記外来遺伝子との間に作動可能に連結されている信号配列を さらに含む、請求項1ないし5のうちいずれか1項に記載の微生物。
- プロテアーゼをコーディングする遺伝子が欠失されている、請求項1ないし5のうちいずれか1項に記載の微生物。
- プロテアーゼをコーディングする遺伝子が、プロモーターと作動可能に連結された血管作動性腸ペプチド(VIP)をコーディングする外来遺伝子で代替された、請求項7に記載の微生物。
- プロテアーゼが、HtrA、PepN、ClpP及びLon から構成された群から選択される1以上である、請求項1ないし5のうちいずれか1項に記載の微生物。
- 栄養要求株(auxotroph)である、請求項1ないし5のうちいずれか1項に記載の微生物。
- ribB、thyA及びglmSなる 構成された群から選択される1以上の遺伝子が欠失された、請求項10に記載の微生物。
- プロモーター、及び前記プロモーターと作動可能に連結された血管作動性腸ペプチド(VIP)をコーディングする外来遺伝子が導入され、プロテアーゼが不活性化されている組み換え微生物であり、乳酸菌である組み換え微生物を含む、ヒトにおいて胃腸管の損傷を引き起こす疾患を予防または治療するための、組成物。
- 前記疾患は、胃腸管炎症を引き起こすものである、請求項12に記載の組成物。
- 前記疾患は、炎症性腸疾患(IBD)及び大腸炎(colitis)からなる群から選択された1以上であるものである、請求項13に記載の組成物。
- 前記炎症性腸疾患は、潰瘍性大腸炎(ulcerative colitis)またはクローン病(Crohn’s disease)であるものである、請求項14に記載の組成物。
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