JP2017535288A - Hnp―1又はhnp−2又はhnp−3をコード化するプラスミドdna、細菌性産生株、鎮痛剤 - Google Patents
Hnp―1又はhnp−2又はhnp−3をコード化するプラスミドdna、細菌性産生株、鎮痛剤 Download PDFInfo
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Abstract
Description
* ペプチドを用いた、痛み及び炎症の治療法(特許文献48)、CRMP−2及びCaV2.2の相互作用を分離し、その結果Nタイプのカルシウムチャンネルの活性化が起こらないにする痛み及び炎症の治療法(特許文献49)、及びLI−CAM、アンキリン及び電位依存性カルシウムチャンネルの相互作用の分離により、軸索の損傷を治療し、神経伝達物質の放出及び痛みの伝達を抑制し、ニューロン内におけるカルシウムポンプをブロックする治療法(特許文献50)、ならびに、鎮痛用の、ナトリウムチャンネルNavl.7のペプチド毒素の類似型(特許文献51)が知られている。
* アンタゴニストIL−31、ヒト化単クローン抗体又はキメラ抗体を使用した、神経組織内の痛み及び炎症の治療法(特許文献52)、前立腺酸性フォスファターゼ(PAP)、その活性型、断片型または誘導体を使用した痛み及び炎症の治療法(特許文献53)。
* CCR2に対する抗体を用いた神経因性疼痛の治療法(特許文献54)、プロサポニンの誘導体であるペプチドを用いた神経障害性疼痛の治療法(特許文献55)、アミノ酸配列Thr−Rl−Lue−Ile−Asp−Asn−Asn−Ala−Thr−Glu−Glu−Ile−Leu−Tyr(ただし、Rlは、神経変性疾患又は髄鞘形成障害に作用を及ぼすD−アラニン)を含むペプチドを用いた治療法(特許文献56)、調整領域と結合した、神経障害性疼痛(VR1, NaV1.8及びTrkA)に関連する標的遺伝子の発現を活性化もしくは抑制15 000756する能力を有する、亜鉛フィンガータンパク質領域をもつタンパク質を用いた治療法(特許文献57)。
* 分離された遺伝子の配列を利用した、神経因性疼痛又は鋭敏化した中枢性疼痛の治療法。この場合、この遺伝子が、力学的にそれぞれ異なる1番目及び2番目の神経因性疼痛又は鋭敏化した中枢性疼痛に応じて、哺乳類の脊髄中で制御される(特許文献58,59,60,61)。
* 慢性疼痛の、ポリペプチドTORCを利用した治療法(特許文献62)、ヒストグラニン及び化学的に安定なその類似型を利用した治療法(特許文献63)、線形及び環形ヒストグラニンペプチド及びそれらをベースとした擬ペプチドを利用した治療法(特許文献64)、IL−10及びIL−4を含む組換えタンパク質を利用した治療法(特許文献65)、IL−10をベースとするポリペプチドを利用した治療法(特許文献66)。
* 急性及び慢性疼痛(様々な形態の疼痛)の、IL−13結合タンパク質を利用した治療法(特許文献67)、lb−12/p40結合タンパク質を利用した治療法(特許文献68)、IL−12/p41結合タンパク質を利用した治療法(特許文献69)、IL−17−結合タンパク質を利用した治療法(特許文献70)、プロスタグランジンE2結合タンパク質を利用した治療法(特許文献71)、二重可変領域をもつ免疫グロブリンを利用した治療法(特許文献72)、プロスタグランジンE2に対して二重可変理領域をもつ免疫グロブリンを利用した治療法(特許文献73)、EE3系タンパク質を利用した、慢性又は急性の疼痛発作との戦い(特許文献74)。
* 受容体のグニアル酸シクラーゼ活性を高めるポリペプチドを利用した内臓性疼痛の治療(特許文献75)。
* IL−1結合タンパク質を用いた神経因性疼痛、骨関節炎痛、炎症性疼痛の治療法(特許文献76)、安定した、可溶性のTNF−αの抗体・抑制剤を用いた、関節炎の炎症過程及びその他の腫瘍壊死因子(TNF−α)媒介疾病又は病態生理学的メカニズム、とくに様々な形態の痛みの治療法(特許文献77)、カルシトニン遺伝子関連ペプチド(CGRP)のヒト化アンタゴニスト抗体を用いた関節炎疼痛の治療(特許文献78)、少なくとも一つのボツリヌス毒素又はそれをベースとしたペプチドを用いた、少なくとも一つの抗癌剤によって誘導された痛みの治療(特許文献79)及びそれにアヘン誘導体を併用した治療法(特許文献80)、Musタンパク質と関連したPAMを用いた疼痛治療(特許文献81)、ガラニン受容体に似た、ポリペプチドGPCR(Gタンパク質共役受容体)を用いた治療法(特許文献82,83,84)、コントゥラキンG(contulakin−G)及びその脱グリコキシル形態を用いた治療法(特許文献85,86)、タンパク質キナーゼCのペプチド抑制剤を使用する治療法(特許文献87)、カリシトニン遺伝子と結びついたペプチドに対して向けられるアンタゴニスト抗体の投与による内臓性疼痛の治療法(特許文献88)。
* 主としてラクトバチルス・ラムノサス(Lactobacillus rhamnosus)を用いた腹痛の治療法(特許文献89)。
* 急性疼痛、すなわち、損傷と不可分に結びついた、一般に何らかの症候としての、新たな、つい最近痛み出した疼痛は、損傷を取り除くことによって消える[Eddy N.B.,Leimbach D.J.//Pharmacol Exp Ther.−Mar;107(3)385−93.−1953]。そこには、手術前後の痛み、外傷後の疼痛、火傷の痛み、分娩時の激痛、脊髄外傷による疼痛、激しい頭痛、HIV/AIDSの痛み、鎌状赤血球クリーゼ、三叉神経症、膵臓炎及びその他の胃腸管の疾患による痛み、心筋梗塞及びその他の心臓疾患に伴う痛み、(診断時及び治療時における)侵襲性介入による痛み、2〜3か月間つづき、痛みが放散する慢性疼痛の激化も含まれる[WHO Normative Guidelines on Pain Management, Geneva June 2007]。
* 慢性疼痛、すなわち、長期間(2〜3か月超)継続する痛み及び痛みの原因を除去したのちも一つの個別疾患とみなされる、例えば炎症痛のような痛み[Eddy N.B.,Leimbach D.J.//Pharmacol Exp Ther.−Mar;107(3):385−93.−1953]で、その際、鎮痛効力の減衰が認められる痛み。(癌患者、HIM/AIDS患者の痛み、筋萎縮性側索硬化症(ALS)、多発性硬化症による痛み、器官障害の最終段階の痛み、広範囲の慢性閉鎖性肺疾患、広範囲の鬱血性心不全、パーキンソン病の痛みを含む)悪性疾患に伴う慢性的痛みが、慢性的疼痛とみなされるほか、悪性疾患と結びつかない以下のような慢性的痛みも慢性疼痛とみなされる:背中の痛み又は腰痛のような慢性筋骨格系疼痛、慢性的変性性関節炎、骨関節炎、リューマチ性関節炎の痛み、筋筋膜疼痛及びリューマチ痛、慢性頭痛、偏頭痛、骨の痛み、神経因性疼痛(神経性圧迫、外傷、神経に障害を受けたのち及び切断後の痛みを含む)、糖尿病性の神経障害に伴う痛み、複合性局所疼痛症候群(タイプI及びタイプII)、骨格筋の痙攣、帯状疱疹後神経痛に伴う痛み、外科手術後の慢性疼痛、内臓痛(体腔拡張に伴う痛み及びさしこみ)、及び鎌状赤血球症に伴う慢性疼痛[WHO Normative Guidelines on Pain Management, Geneva June 2007]。
* RNAポリメラーゼとDNAとの相互作用を改善することを通じて、発現レベルを増強するためのエンハンサー
* エンハンサーの機能を調整するためのインシュレーター
* 転写レベルを低下させるための、例えば組織特異的発現のための、サイレンサーもしくはその断片
* イントロンを含む、プロモーターまでの5’非翻訳領域
* mRNAの安定性を高め、標的遺伝子の発現を増強するための、イントロンを含む、プロモーター下流の非翻訳領域
C(micg/mL)=40A260K
ただし、A260は波長260nmで測定された薬剤の光学的密度;K(micg/mL)は、50micg/mLのDNA(水中の、50micg/mLの二本鎖DNA)に対するもの;40は被験薬剤の希釈。
3.1. ホットプレートテスト
ホットプレートテストにより、αディフェンシンHNP−1又はHNP−2又はHNP−3をコード化するプラスミドDNAの鎮痛活性の検査が行われた。
1群:ネガティブコントロール(生理食塩水を投与)
2群:pVAX1seq3
3群:pVR1012seq4
4群:pVR1012seq5
5群:pVAXlseq6
6群:pVR1012seq9
7群:pVAX1seq10
8群:pVAX1seq11
9群:pVR1012seq12
10群:pcDNA3.1+seq11
11群:pcDNA3.1+(var)seq12
12群:アナルギン(50mg/kg)
13群:モルヒネ塩酸塩(10mg/kg)
14群:pVAX1
15群:pVR1012
16群:pcDNA3.1+
17群:pcDNA3.1+(var)
プラスミドDNAが5mg/kgずつ投与された。
ホットプレートメーター一式(Hotplate Analgesia Meter, ColumbusInstruments,USA)が用いられた。
血漿中のβエンドルフィン濃度の変化が、鎮痛効果を評価するための基準であるので[癌患者の急性疼痛及び慢性疼痛症候群における鎮痛効果のマーカーとしてのβエンドルフィン/Z.V.パ−ヴロワ(及びその他)//臨床医学の諸問題−2007年−NI−ISSN 1817−8359]、プラスミドDNA投与後の被験マウス(複数)の血清中におけるβエンドルフィン濃度検査が、HNP−2又はHNP−3をコード化するプラスミドDNA(pVR1012seq4)を投与した場合の実例において、ELISA Kit for Beta−Endorpin (bEP)Mus musculus (Mouse) CEA806Mu(Life science Inc.)を用いて実施された。
Claims (5)
- 原核生物の要素、複写開始点、レポーター遺伝子、真核生物の要素、強力なプロモーター、mRNAのリーダー配列及び上記諸要素のための制御配列、目的遺伝子のクローン化のための一つのサイト、望ましくはそのための複数のサイト、分析用のプライマー植付け用の一つのサイト、望ましくはそのための複数のサイトを含む骨組によって構成された、ならびに分泌配列及び、哺乳類用にコドンが最適化されたαディフェンシンHNP−1又はHNP−2又はHNP−3をコード化する断片より成るポリヌクレオチド及びターミネーター配列によって構成された、哺乳類の細胞において一過性発現を行うプラスミドDNA(諸形態)。
- プレプロタンパク質が、SEQ ID NO:1又はSEQ ID NO:2又はSEQ ID NO:7又はSEQ ID NO:8により構成されていることを特徴とする、請求項1に記載されているプラスミドDNA。
- ポリヌクレオチドが、SEQ ID NO:3又はSEQ ID NO:4又はSEQ ID NO:5又はSEQ ID NO:6又はSEQ ID NO:9又はSEQ ID NO:10又はSEQ ID NO:11又はSEQ ID NO:12によって構成されていることを特徴とする、請求項1又は請求項2に記載されているプラスミドDNA。
- 細菌の細胞をベースとする、請求項1又は請求項2又は請求項3に記載されたプラスミドDNAの産生株。
- 製薬上許容できる添加剤を含む、請求項1又は請求項2又は請求項3に記載された、有効量のプラスミドDNAをベースとした、哺乳類、特にヒトに用いられる鎮痛剤。
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PCT/RU2015/000756 WO2016076761A1 (ru) | 2014-11-10 | 2015-11-10 | Плазмидная днк, кодирующая hnp-1, либо hnp-2, либо hnp-3, бактериальный продуцент, анальгетическое средство (варианты) |
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