JP2020526554A - 疼痛を管理するための方法 - Google Patents
疼痛を管理するための方法 Download PDFInfo
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Abstract
【選択図】なし
Description
本発明は、米国国立衛生研究所によって授与された助成番号DE022903の下で米国政府の支援を受けてなされた。米国政府は、本発明におけるある特定の権利を有する。
本出願は、本開示の別個の部分として、その全体が参照により組み込まれるコンピュータ可読形式の配列表(ファイル名:51774A_Seqlisting.txt、サイズ:73,7002バイト、2018年7月13日作成)を含む。
炭酸アンヒドラーゼ10(CA10)は、炭酸アンヒドラーゼ(CA)スーパー遺伝子ファミリーのメンバーであり、触媒として不活性である3つのCAアイソフォームのうちの1つである。CA10は中心的な炭酸アンヒドラーゼモチーフを保持しているが、酵素活性に重要な触媒亜鉛配位残基を欠いている。CA10の機能は、以前は不明のままであるであった。配列比較により、ヒト(Homo sapiens)、ラット(Rattus norvegicus)、およびマウス(Mus musculus)のCA10タンパク質間で100%の同一性が、ならびにゼブラフィッシュ(Danio rerio)とアミノ酸レベルで90%の同一性が明らかになった。ヒトCA10をコードする9つの転写産物があり、結果として7つの機能的アイソフォームになる。ヒトCA10の核酸およびアミノ酸の配列は、Genbank受入番号NM_020178(配列番号3)、NP_064563(配列番号4)、NM_001082534(配列番号5)、NP_001076003(配列番号6)、NM_001082533(配列番号7)およびNP_001076002(配列番号8)に記載されており、ヒトCA10のアミノ酸配列は、UniProtKB Q9NS85(配列番号9)においても提供されている。
「ベクター」または「発現ベクター」は、宿主細胞に導入するための核酸(DNAまたはRNA)を含む任意のタイプの遺伝子コンストラクトである。様々な実施形態において、発現ベクターは、ウイルスベクター、すなわち、核酸送達ビヒクルとして機能することができるウイルスゲノムの全部または一部を含むウイルス粒子である。また、関心対象の遺伝子産物をコードする外来性核酸(複数可)を含むウイルスベクターは、組換えウイルスベクターと称される。当技術分野で理解されるであろうように、いくつかの文脈において、「ウイルスベクター」という用語(および同様の用語)は、ウイルスカプシドの非存在下でのベクターゲノムを指すために使用され得る。本開示の文脈で使用するためのウイルスベクターには、例えば、レトロウイルスベクター、単純ヘルペスウイルス(HSV)系ベクター、パルボウイルス系ベクター、例えば、アデノ随伴ウイルス(AAV)系ベクター、AAV−アデノウイルスキメラベクター、およびアデノウイルス系ベクターが含まれる。これらのウイルスベクターはいずれも、例えば、Sambrook et al.,Molecular Cloning,a Laboratory Manual,2d edition,Cold Spring Harbor Press,Cold Spring Harbor,N.Y.(1989)、Ausubel et al.,Current Protocols in Molecular Biology,Greene Publishing Associates and John Wiley&Sons,New York,N.Y.(1994)、Coen D.M,Molecular Genetics of Animal Viruses in Virology,2nd Edition,B.N.Fields(editor),Raven Press,N.Y.(1990)およびこれらに引用されている参考文献に記載されている標準的な組換えDNA技術を使用して調製することができる。さらに、Gatewayクローン形成(Hartley et al.,Genome Res 2000,10:1788−1795)および/または「組換え工学」システム(Copeland et al.,Nat Rev Genet 2001,2:769−779)を用いた標的ゲノム領域の相同組換え媒介性クローン形成および操作の応用を用いた5‘および3’調節配列を含む遺伝子全体を含む、ヒトおよび他の宿主種由来の大型ゲノムコード配列を使用してウイルスベクターを調製することができる。
「疼痛」は、一般に、持続期間、原因、および/または身体の患部の観点から説明される。本発明は、神経因性疼痛(例えば、体性感覚神経系の病変または疾患により開始または発症する疼痛)、炎症性疼痛(例えば、炎症性メディエーターによる侵害受容性疼痛経路の活性化および/または感作により発症する疼痛)、および/または侵害受容性疼痛(例えば、組織の傷害または損傷によって発症する疼痛)を含むあらゆるタイプの疼痛の治療を含む。多くの疼痛障害また疼痛事故は簡単に分類することができず、これらの一般的なクラスと重複する態様または特徴を伴うことがある。また、疼痛は、体内の位置に関して分類され、体性痛は、体表または筋骨格組織の痛覚受容体の活性化から結果として生じるのに対し、内臓痛は内臓で感じられ、通常、胸部、骨盤、または腹部の痛覚受容体の活性化によって発症する。
本開示はさらに、1つ以上の鎮痛薬候補ペプチドをコードする複数の遺伝子移入ベクターを含むストックを提供する。ストックは、ベクターの任意の所望の力価を有することができ、通常、ウイルスベクターの脈絡においてプラーク形成単位(pfu)で測定される。通常、ストックは、約105pfu/ml〜約108pfu/mlを有する。いくつかの実施形態において、ストックは、均質である。いくつかの実施形態において、候補鎮痛ペプチド(複数可)(またはその前駆体)をコードするDNA配列は、ストック内のベクター間で異なる。様々な実施形態において、ストック内のベクター間で候補鎮痛ペプチド(複数可)(またはその前駆体)をコードするそれぞれのDNA配列は、無作為または半無作為ペプチドライブラリーを規定する。任意選択的に、DNA配列は、カルボキシルアンヒドラーゼペプチドの前駆体をコードする。
様々な態様において、発現ベクターは、生理学的に許容される(すなわち、薬理学的に許容される)担体、緩衝剤、賦形剤、または希釈剤を含む組成物(例えば、医薬組成物)で提供される。任意の好適な生理学的に許容可能な(例えば、薬学的に許容可能な)担体を本開示の文脈内で使用することができ、そのような担体は当技術分野で周知されている。担体の選択は、部分的に、本組成物が投与される特定の部位、および本組成物を投与するために使用される特定の方法によって決定されるだろう。本組成物はまた、宿主細胞への発現ベクターの取り込みを促進する薬剤も含むことができる。好適な組成物製剤には、水性および非水性溶液、抗酸化剤、緩衝剤、静菌剤、および製剤を血液と等張にする溶質を含有し得る等張無菌溶液、ならびに懸濁剤、可溶化剤、増粘剤、安定剤、および防腐剤を含み得る水性および非水性無菌懸濁液が含まれる。本組成物は、アンプルおよびバイアルなどの単位用量または複数用量の密封容器で提供でき、例えば、使用する直前に水などの無菌液体担体を追加することのみを必要とする凍結乾燥された(凍結乾燥)状態で保存され得る。CA8、CA8断片、CA10またはCA11をコードする発現ベクターを含む組成物は、一態様において、組成物の使用に関する指示を提供する包装材料とともに容器内に配置される。一般に、そのような指示には、試薬濃度、ならびにある特定の実施形態において、本組成物を再構成するのに必要になり得る賦形剤成分または希釈剤(例えば、水、生理食塩水、またはPBS)の相対量を説明する具体的な表現が含まれる。
本実施例は、炭酸アンヒドラーゼ8(CA8ヒト遺伝子記号、Car8げっ歯類オルソログ)、炭酸アンヒジラーゼ10(CA10ヒト遺伝子記号、Car10げっ歯類オルソログ)および炭酸アンヒドラーゼ11(CA11ヒト遺伝子記号、Car11げっ歯類オルソログ)が、ITPR1サイトソルの遊離カルシウムシグナル伝達経路を調節することを実証する。ITPRは、炎症性疼痛挙動において重要な役割を担っているITPRからのイノシトール1,4,5−三リン酸(IP3)シグナル伝達分子および細胞内カルシウム放出を発生させる向代謝性受容体活性化から生じるシグナルを伝達すると考えられている。Zhuang et al.,PLoS One,2015。本明細書で初めて記載されたデータは、CA8/Car8)、CA8/Car8断片(CA8−204を含む)、CA10/Car10、およびCA11/Car11が、ITPR1カルシウム放出チャネルのIP3活性化、細胞内カルシウム放出を阻害するように、驚くべきことに、細胞内カルシウム放出を阻害することにより治療用鎮痛薬(例えば、モルヒネおよびクロニジン)に対する鎮痛応答を阻害するように、さらにこれらのCAペプチドがモデルにおいて顕著な鎮痛を生じ、かつ慢性神経因性疼痛を処置または予防するように機能することを示す。また驚くべきことに、CA8/Car8断片(CA8−204を含む)およびCA10/Car10はITPR1に結合しない(共免疫沈降によって実証)が、CA8(Car8)ペプチドとは明確に対照的に、CA8/Car8断片(CA8−204を含む)およびCA10/Car10ペプチドの細胞内過剰発現は、ホルスコリンおよびATP刺激性細胞内カルシウム放出に応答してITPR1活性化(リン酸化)を阻害する。
動物:すべての実験と手順は、意識のある動物の実験的疼痛に関する研究者のための現行の指針によって行われ、マイアミ大学の動物管理使用委員会によって承認された。体重20〜35グラムの雄の成C57BL/6マウスをJackson Laboratories(Bar Harbor,ME)から取得し、食物および水を自由に摂取できるホームケージ環境内で維持した。動物を、湿度およい温度が制御されたウイルス/抗原非含有施設内で12時間ごとの明暗周期において飼育した。動物を、手術前に7日間順化させ、検査前に実験装置に慣れさせた。
V5−Car10およびV5−CA10タンパク質の過剰発現は、インビトロでのホルスコリン誘導性pITPR1を阻害する。本明細書に記載の結果は、例えば、IP3リガンドに対するITPR1の応答を増強するリン酸化によるITPR1の活性化(pITPR1)の調節に及ぼすCar10の効果を検討するための薬力学的バイオアッセイの使用を実証する。HEK293細胞に、Car10およびCA10を過剰発現するAAV8−V5ベクター、空ベクターおよび対照としてのビヒクルをトランスフェクトした。外来性と内在性のCA10/Car10発現を区別するために、V5配列をCar10またはCA10のC末端領域に挿入した。ウェスタンブロット分析により、ホルスコリンは用量依存的様式でpITPR1レベルを増加させることが実証された(図1A)。V5タグを使用して、V5−Car10およびV5−CA10ベクターのトランスフェクション後にタンパク質の過剰発現を検出した(図1B)。Car10およびCA10の過剰発現は、HEK293細胞内ホルスコリン誘導性ITPR1リン酸化を低減させたのに対し、空ベクターはITPR1リン酸化を変化させなかった(図1C)。
本明細書に記載するデータは、(1)インビトロでのCA8断片(CA8−204)、CA10、およびCar10タンパク質の過剰発現が、ホルスコリンに応答してSer−1755でのITPR1の調節ドメインのリン酸化を阻害すること、(2)CA8断片(CA8−204)、CA10、およびCar10の過剰発現が、インビトロでのATP刺激性細胞内カルシウム放出を阻害すること、(3)炎症性および神経因性疼痛モデルを使用した、C57BL/6Jマウスへの坐骨神経注射を介した侵害受容器へのAAV8−V5−CA10およびAAV8−V5−Car10の遺伝子移入は、顕著な鎮痛を生じ、痛覚過敏抑制を予防すること、を初めて実証する。これらの発見は、CA8断片(CA8−204)、CA10、およびCar10が侵害受容および疼痛に重要なITPR1サイトソル遊離カルシウムシグナル伝達経路を調節することを初めて確立する。
以下の実施例は、本明細書に記載のCA8断片をコードするアデノ随伴ウイルスベクター(AAV8−FLAG−CA8204C(CA8204C)およびAAV8−flag−CA8204G(CA8204G)の投与が、臨床的に関連する動物モデルであるカラギーナン炎症疼痛モデルにおいて鎮痛痛覚過敏抑制を生じることを実証する。
本実施例は、共免疫沈降により実証されるように、CA10がRYRおよびpRYRに結合することを実証する。リポフェクタミン(LTX)を使用して、NBL細胞にAAV−V5−CA10およびAAV−V5−Car10をトランスフェクトした。トランスフェクションの48時間後に細胞タンパク質を抽出した。
本実施例は、V5−CA10タンパク質の過剰発現がホルスコリン誘導性pITPR1をインビトロで阻害することを実証する。
以下の実施例は、CA10の過剰発現が疼痛メディエーターに応答したITPR1およびRYR媒介性カルシウム放出を阻害することを実証する。驚くべきことに、本明細書に記載の試験は、NBL細胞において、5HT媒介性RYR依存性カルシウム放出がリアノジンによってほぼ完全に阻害されることを実証する。その上、また、NBL細胞におけるV5−CA10の過剰発現は、5HT媒介性カルシウム放出を阻害することが観察された。それゆえ、NBL細胞における5HT媒介性シグナル伝達は、主にRYRを経ているようである。
pCMV−N−flag−CA8−204GおよびpCMV N−flag−CA8−204Cの構築。SalI部位とKpnI部位とを含むプライマーを、rs6471859 SNPでの「G」を有する完全長の代替変異体(CA8−204)をpCMV−N−flagベクター(Clontech)内へ構築するために設計した。部位特異的突然変異誘発(Invitrogen)を利用して、rs647859に「C」対立遺伝子を有するエキソン3で終わる新規の断片を生成するpCMV−N−flag−CA8−204Cを構築した。図38を参照されたい。
Claims (37)
- 疼痛の治療または予防を必要とする対象において、疼痛を治療または予防する方法であって、炭酸アンヒドラーゼ10または炭酸アンヒドラーゼ11を産生するように前記核酸が発現されるように、炭酸アンヒドラーゼ10または炭酸アンヒドラーゼ11をコードする核酸配列を含む発現ベクターを前記対象に投与することを含む、方法。
- 前記対象が、ヒトである、請求項1に記載の方法。
- 前記発現ベクターが、ウイルスベクターである、請求項1または請求項2に記載の方法。
- 前記ウイルスベクターが、アデノ随伴ウイルスベクターである、請求項3に記載の方法。
- 前記ウイルスベクターが、単純ヘルペスウイルスベクターである、請求項3に記載の方法。
- 前記炭酸アンヒドラーゼ10または炭酸アンヒドラーゼ11をコードする核酸配列が、CMVプロモーター、TrkAプロモーター、TrkB、TrkCプロモーター、Nav1.9プロモーター、Nav1.8プロモーター、Nav1.7プロモーター、NMDAプロモーター、アドビリンプロモーター、CGRPプロモーター、5HTプロモーター、NK1プロモーター、ASIC3プロモーター、NPYプロモーター、およびNF200プロモーターからなる群から選択されるプロモーターに作動可能に連結されている、請求項1〜5のいずれか1項に記載の方法。
- 前記疼痛が、神経因性疼痛である、請求項1〜6のいずれか1項に記載の方法。
- 前記疼痛が、炎症性疼痛である、請求項1〜6のいずれか1項に記載の方法。
- 前記疼痛が、癌または脊髄損傷によって引き起こされる、請求項1〜6のいずれか1項に記載の方法。
- 前記発現ベクターを前記対象の後根神経節に投与することを含む、請求項1〜9のいずれか1項に記載の方法。
- 関節内注射を介して前記発現ベクターを投与することを含む、請求項1〜9のいずれか1項に記載の方法。
- 前記発現ベクターを経口投与することを含む、請求項1〜9のいずれか1項に記載の方法。
- 前記発現ベクターを三叉神経節に投与することを含む、請求項1〜9のいずれか1項に記載の方法。
- 末梢神経注射を介して前記発現ベクターを投与することを含む、請求項1〜9のいずれか1項に記載の方法。
- 疼痛が生じる部位にカテーテルを介して前記発現ベクターを投与することを含む、請求項1〜9のいずれか1項に記載の方法。
- 疼痛が生じる部位に針を介して前記発現ベクターを投与することを含む、請求項1〜9のいずれか1項に記載の方法。
- 前記発現ベクターを投与するための画像解析の使用を含む、請求項1〜9のいずれか1項に記載の方法。
- 必要とする対象において疼痛を処置または予防する方法であって、前記断片を産生するように前記核酸が発現されるように、前記対象に、炭酸アンヒドラーゼ8の断片をコードする核酸配列を含む発現ベクターを投与することを含む、方法。
- 前記対象が、ヒトである、請求項18に記載の方法。
- 前記発現ベクターが、ウイルスベクターである、請求項18または請求項19に記載の方法。
- 前記ウイルスベクターが、アデノ随伴ウイルスベクターである、請求項20に記載の方法。
- 前記ウイルスベクターが、単純ヘルペスウイルスベクターである、請求項20に記載の方法。
- 前記炭酸アンヒドラーゼ8の断片をコードする核酸配列が、CMVプロモーター、TrkAプロモーター、TrkBプロモーター、TrkCプロモーター、Nav1.9プロモーター、Nav1.7プロモーター、Nav1.8プロモーター、NMDAプロモーター、アドビリンプロモーター、CGRPプロモーター、5HTプロモーター、NK1プロモーター、ASIC3プロモーター、NPYプロモーター、およびNF200プロモーターからなる群から選択されるプロモーターに作動可能に連結されている、請求項18〜22のいずれか1項に記載の方法。
- 前記疼痛が、神経因性疼痛である、請求項18〜23のいずれか1項に記載の方法。
- 前記疼痛が、炎症性疼痛である、請求項18〜23のいずれか1項に記載の方法。
- 前記疼痛が、癌または脊髄損傷によって引き起こされる、請求項18〜23のいずれか1項に記載の方法。
- 前記発現ベクターを前記対象の後根神経節に投与することを含む、請求項18〜26のいずれか1項に記載の方法。
- 関節内注射を介して前記発現ベクターを投与することを含む、請求項18〜26のいずれか1項に記載の方法。
- 前記発現ベクターを経口投与することを含む、請求項18〜26のいずれか1項に記載の方法。
- 前記発現ベクターを三叉神経節に投与することを含む、請求項18〜26のいずれか1項に記載の方法。
- 末梢神経注射を介して前記発現ベクターを投与することを含む、請求項18〜26のいずれか1項に記載の方法。
- 疼痛が生じる部位にカテーテルを介して前記発現ベクターを投与することを含む、請求項18〜26のいずれか1項に記載の方法。
- 疼痛が生じる部位に針を介して前記発現ベクターを投与することを含む、請求項18〜26のいずれか1項に記載の方法。
- 前記発現ベクターを投与するための画像解析の使用を含む、請求項18〜22のいずれか1項に記載の方法。
- 前記炭酸アンヒドラーゼ8の断片が、CA8−204である、請求項18〜34のいずれか1項に記載の方法。
- 前記炭酸アンヒドラーゼ8の断片が、CA8−204CまたはCA8−204Gである、請求項35に記載の方法。
- 前記炭酸アンヒドラーゼ8の断片が、CA8−202またはCA8−203である、請求項18〜34のいずれか1項に記載の方法。
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WO2008010637A1 (en) * | 2006-07-19 | 2008-01-24 | Industry-Academic Cooperation Foundation, Yonsei University | Composition for attenuating neuropathic pain comprising a recombinant vector expressing gad65 |
US20090324730A1 (en) * | 2008-06-26 | 2009-12-31 | Fallon Joan M | Methods and compositions for the treatment of symptoms of complex regional pain syndrome |
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GERALD Z. ZHUANG ET AL.: "Carbonic Anhydrase-8 Regulates Inflammatory Pain by Inhibiting the ITPR1-Cytosolic Free Calcium Path", PLOS ONE, vol. 10, no. 3, JPN7022002328, 2015, pages 0118273, ISSN: 0004937381 * |
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