JP2012255016A - 腸疾患の治療 - Google Patents
腸疾患の治療 Download PDFInfo
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- JP2012255016A JP2012255016A JP2012181002A JP2012181002A JP2012255016A JP 2012255016 A JP2012255016 A JP 2012255016A JP 2012181002 A JP2012181002 A JP 2012181002A JP 2012181002 A JP2012181002 A JP 2012181002A JP 2012255016 A JP2012255016 A JP 2012255016A
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Abstract
【解決手段】RNA干渉を媒介し得る、短い干渉RNA(siRNA)、二本鎖RNA(dsRNA)、マイクロRNA(miRNA)、antagomir、及び短いヘアピンRNA(shRNA)分子等を、過剰増殖性疾患、特に結腸直腸ガン;自己免疫性及び炎症性腸疾患(IBD)、特にクローン病;大腸炎、特に潰瘍性大腸炎;過敏性腸症候群;腸の感染性疾患、例えば偽膜性大腸炎、アメーバ症、または腸結核等;結腸ポリープ;憩室疾患;便秘症;腸閉塞;吸収不良症候群;直腸疾患;並びに下痢;を含む腸症状の治療のための薬剤の調製に用いる。
【選択図】なし
Description
RNAi干渉とは、二本鎖RNA(dsRNA)によって媒介される、配列特異的な転写後遺伝子サイレンシングの過程を表す。1990年代初期における、植物における当該現象の発見後、Andy FireとCraig Melloは、dsRNAが、線虫において極めて効率的な方法で遺伝子発現を特異的且つ選択的に抑制することを証明した(Fireら, 1998)。第一鎖(センスRNA)の配列は、標的メッセンジャーRNA(mRNA)の対応する領域のものに一致した。第二鎖(アンチセンスRNA)は、前記mRNAに相補的であった。その結果生じたdsRNAは、相当する一本鎖RNA分子(特に、アンチセンスRNA)よりも、数桁の量でより効率的であることが分かった。
インターロイキン-12(IL-12)は、IL-12の生物学的活性に必須のジスルフィド結合によって連結された、40kDaのサブユニット(IL12-p40と称される)と35kDaのサブユニット(IL12-p35と称される)とからなる、ヘテロ二量体の70kDaの糖タンパク質(IL12-p70)である。
動物モデル及びクローン病の患者における抗IL-12の臨床効果から得られた先の証拠(Mannonら, 2004)は、クローン病に対する将来の治療法の標的としてのIL-12の重要性を強調している。
<siRNAによるIL-12レベルの調節>
IL-12発現を標的とするsiRNAは、T細胞活性を調節する種々の治療的in vitro、ex vivo、及びin vivo方法に用いられ得、それにより、哺乳類被験者における免疫疾患の治療のための治療的手法における使用を有する、修飾樹状細胞(DC)を獲得するためにすでに用いられている(WO 03/104456;Hillら, 2003)。成熟DCにおいてIL-12発現を標的とするsiRNAは、成熟DCによって促進されるナチュラルキラー細胞インターフェロンγ(IFN-γ)におけるIL-12に対する重大な役割を明らかにしている(Borgら, 2004)。さらに、siRNAを含むIL12-p35インヒビターは、驚くべきことに、前脂肪細胞の脂肪細胞への分化及び脂肪細胞におけるトリグリセリドの蓄積を阻害することを示している(WO 03/104495)。
ある実施態様において、本発明は、サイトカインIL-12のp35またはp40サブユニットのいずれかのmRNA発現を干渉することに向けられ、且つ産生されたタンパク質の量を最終的に調節するsiNAまたは類似の化学的に合成された物質に関する。前記siRNA及び関連化合物を含む組成物及び方法は、IL-12の過剰発現をともなう疾患、例えば自己免疫疾患及び炎症性腸疾患(IBD)等、特にクローン病の治療を意図する。
例えば、siNAが遺伝子の発現を選択的に低下させるまたは阻害する場合、前記遺伝子は本発明に係るsiNAによって「標的とされる」。厳しい条件下で、siNAが遺伝子転写物にハイブリダイゼーションする場合、siNAは前記遺伝子を標的とする。siNAを、遺伝子を標的とする能力について、in vitroまたはin vivoのいずれかにおいて調べることができる。
siNAを当該技術分野で既知の任意の方法によって合成することができる。好ましくは、RNAは、適切に保護されたリボヌクレオシド・ホスホラミダイト及び従来のDNA/RNA合成機を用いることによって化学的に合成される。さらに、siRNAは、Proligo社(Hamburg, Germany)、Dharmacon Research社(Lafayette, CO, USA)、Glen Research社(Sterling, VA, USA)、ChemGenes社(Ashland, MA, USA)、Cruachem社(Glasgow, UK)、Qiagen社(Germany)、Ambion社(USA)、及びInvitrogen社(Scotland)を含むが、これに制限されない商業的RNAオリゴ合成供給元から得ることができる。あるいは、本発明のsiNA分子を、プロモーターの制御下で、逆相補的siNA配列を含むベクターを用いて細胞にトランスフェクションすることによって、細胞中で発現させることができる。発現させたら、当該技術分野において公知の技術を用いることによって、前記細胞から前記siNAを単離することができる。
本発明のsiNAは、1つ以上の修飾されたヌクレオチド及び/または非リン酸ジエステル結合を含んでよい。当該技術分野で公知の化学修飾は、前記siNAの安定性、有効性、及び/または細胞への取込み量を増大させ得る。当業者は、RNA分子に組み込まれてよい他の種類の化学修飾を知っているであろう(修飾の種類の概説のために、国際文献WO 03/070744及びWO 2005/045037を参照)。
siRNA干渉の特異性を調べるために、標的遺伝子を発現する細胞培養物を使用した。
直腸内siNA送達試験を、GFP C57BL/6-TG(ACTB-EGFP)マウスにおいて実施した。このトランスジェニックマウス系統は、「The Jackson Laboratory」からもたらされた。この導入遺伝子に対してホモのマウスは生後最初の2週間以内に死ぬため、トランスジェニックマウスを用いている。「増強した」GFP(EGFP)cDNAを有するトランスジェニックマウス系統は、ニワトリのβアクチン・プロモーターとサイトメガロウイルス・エンハンサーの制御下で、赤血球と毛髪を除いた組織のすべてが励起光の下で緑色に見える。この系統をC57BL/6マウスにおいて作製した。増強した緑色蛍光タンパク質(EGFP)をコードする当該系統cDNAを、ニワトリのβアクチン・プロモーターとサイトメガロウイルス・エンハンサーに隣接させた。ウシのグロビン・ポリアデニル化シグナルもまた、当該コンストラクト中に含まれた。当該PCRプライマー中に含まれるEco RIサイトを用いて、増幅したEGFP cDNAを、ニワトリのβアクチン・プロモーター、サイトメガロウイルス・エンハンサー、βアクチンイントロン、及びウシのグロビン・ポリアデニル化シグナルを含むpCAGGS発現ベクター中に導入した。前記プロモーターとコード配列を有する全挿入部分を、Bam HIとSal Iで切断し、ゲル精製した。
本発明は、1つ以上のsiNA分子種の投与を同時に含んでもよい。これらの種を選択し、1つ以上の標的遺伝子を標的とすることができる。
<実施例1:siNAの設計>
IL12-p35(インターロイキン12A、ナチュラルキラー細胞刺激因子1、細胞毒性リンパ細胞成熟因子1、p35)及びp40(インターロイキン12B、ナチュラルキラー細胞刺激因子2、細胞毒性リンパ細胞成熟因子2、p40)サブユニットに対応するGenBank登録番号は、それぞれNM_000882及びNM_002187である。
IL12-p35標的遺伝子の阻害を測定するために、図1中に含まれるsiRNAのパネルを細胞培養中で分析した。最高の特性を有するsiRNAを選んで試験し、SW480等の適切な細胞培養に適用した。前記標的遺伝子へのsiRNAの効果を、メーカーのプロトコールに従ったRT-PCRによって分析した。当該遺伝子標的転写物レベルを、ハウスキーピング遺伝子として18Sを用いることによって標準化した。図2は、試験された異なるsiRNAのいくつか、及び前記標的遺伝子の干渉におけるそれらの異なる有効性を含む。これらの結果は、p35を発現するSW480細胞における図1の配列番号8及び配列番号17に相当する。当該値は、コントロール遺伝子発現に対してsiRNA干渉の際に標準化されたmRNAレベルの平均パーセンテージ、及びそれらの中間標準偏差(SEM)を表す。当該siRNA処理後のp35転写物のレベルは、コントロール細胞と比較してSW480細胞において、配列番号8及び配列番号17に対応するsiRNAで非常に低下した。当該遺伝子発現の減少は、siRNAサイレンシングの効率に依存する。実際に、配列番号8のsiRNA処理により、p35遺伝子発現は、コントロールと比較して24時間で56%まで減少した。
IL12-p40標的遺伝子の阻害を測定するために、図1中に含まれるsiRNAのパネルを分析した。前述のように設計した最高の特性を有するsiRNAを、ヒト及びマウス細胞において試験した。p40転写物レベルをRT-PCRで分析し、ハウスキーピング遺伝子として18Sを用いることによって標準化した。これらの結果は、p40を発現するSW480細胞における配列番号67及び配列番号79(図3A)、並びにp40を発現するC2C12細胞における配列番号86及び配列番号87(図3B)に相当する。配列番号86及び配列番号87のsiNA分子は、当該図中に記載されるように、2チミジンヌクレオチド3’突出を有する。
腸内の適切なsiRNA送達を確認するために、siRNA適用を行った。当該siRNA効果を確認するために、小腸サンプルをOCT培地中に回収し、前述のように分析した。GFP遺伝子転写の下方制御を確認することが目標であるため、siRNA適用後に、蛍光量を測定した。当該実験プロトコールの間、二次的効果は当該動物において観察されなかった。
さらに、小腸と同じ方法で、大腸を分析した。大腸における当該siRNA効果を確認するために、siRNA適用後に、蛍光の測定によってGFPの下方制御を確認するために、OCT培地中に回収されたサンプルを分析した。当該結果は、コントロールマウスと比較して、蛍光の有意な減少を示す(図6)。さらに、当該用量を125μgの2回適用で投与し、最初の注入の48時間後に分析した場合、当該減少は単回siRNA投与後に得られたものと非常に類似しており、当該処理の有効性を示している。
Claims (47)
- 腸疾患の治療の有効な方法であって、直腸内にRNA干渉を引き起こす化合物を患者へ投与する工程を含む方法。
- 前記疾患が小腸の疾患である、請求項1に記載の方法。
- 前記疾患が大腸の疾患である、請求項1に記載の方法。
- 前記疾患が直腸の疾患である、請求項1に記載の方法。
- 前記疾患が、過剰増殖性疾患、特に結腸直腸ガン;自己免疫性及び炎症性腸疾患(IBD)、特にクローン病;大腸炎、特に潰瘍性大腸炎;過敏性腸症候群;腸の感染性疾患、例えば偽膜性大腸炎、アメーバ症、または腸結核等;結腸ポリープ;憩室疾患;便秘症;腸閉塞;吸収不良症候群;直腸疾患;並びに下痢;を含む群から選択される、請求項1に記載の方法。
- 前記化合物が、治療を必要とする患者において、変化したレベルを有する標的遺伝子の発現を調節する、請求項1から5のいずれか一項に記載の方法。
- 前記標的遺伝子発現が樹状細胞以外の細胞において調節される、請求項6に記載の方法。
- 前記標的遺伝子発現が腸管上皮細胞において調節される、請求項7に記載の方法。
- 前記化合物がsiNAである、請求項1から8のいずれか一項に記載の方法。
- 前記siNAがsiRNAである、請求項9に記載の方法。
- 前記siNAがdsRNAである、請求項9に記載の方法。
- 前記siNAがshRNAである、請求項9に記載の方法。
- 前記化合物がmiRNAレベルを調節する、請求項1から12のいずれか一項に記載の方法。
- 前記化合物が修飾されたオリゴヌクレオチドを含む、請求項1から13のいずれか一項に記載の方法。
- 前記siNAが40塩基対以下の長さである、請求項9から12のいずれか一項に記載の方法。
- 前記siNAが3’突出部を有する、請求項9から12のいずれか一項に記載の方法。
- 前記3’突出部がジヌクレオチドである、請求項16に記載の方法。
- 前記ジヌクレオチド突出部がチミジンヌクレオチドから構成される、請求項17に記載の方法。
- 複数の種の化合物を用いる、請求項1から18のいずれか一項に記載の方法。
- 前記複数の種が同じmRNA種に方向づけされる、請求項19に記載の方法。
- 前記複数の種が異なるmRNA種に方向づけされる、請求項19に記載の方法。
- 前記化合物が、炎症性腸疾患(IBD)に関わる標的遺伝子の発現を調節する、請求項1から21のいずれか一項に記載の方法。
- 前記IBDがクローン病である、請求項22に記載の方法。
- 前記標的遺伝子がインターロイキン12である、請求項22または23に記載の方法。
- 前記化合物がsiNAである、請求項22から24のいずれか一項に記載の方法。
- 前記siNAが配列番号1から配列番号85からなる群から選択される、請求項25に記載の方法。
- 前記siNAが40塩基対以下の長さであり、且つ配列番号1から配列番号85からなる群から選択されるヌクレオチド配列を含む、請求項25に記載の方法。
- 前記siNAが前記インターロイキン12の35kDaサブユニット(IL12-p35)に方向づけされ、且つ配列番号1から配列番号33からなる群から選択されるヌクレオチド配列を含む、請求項27に記載の方法。
- 前記siNAが前記インターロイキン12の40kDaサブユニット(IL12-p40)に方向づけされ、且つ配列番号34から配列番号85からなる群から選択されるヌクレオチド配列を含む、請求項27に記載の方法。
- 腸疾患の治療のための薬剤の調製における、RNA干渉を引き起こす化合物の使用であって、前記化合物を患者に対して直腸内に投与する使用。
- 腸疾患の治療のための薬剤の調製における、IL-12を標的とするsiNAの使用。
- 前記腸疾患が炎症性腸疾患(IBD)である、請求項31に記載の使用。
- 前記IBDがクローン病である、請求項32に記載の使用。
- 前記siNAが配列番号1から配列番号85からなる群から選択される、請求項31から33のいずれか一項に記載の使用。
- 配列番号1から配列番号85の群から選択されるヌクレオチド配列を含む、インターロイキン12に方向づけされたRNAi化合物。
- 前記RNAiがdsRNA、siRNA、またはshRNAである、請求項35に記載の化合物。
- 配列番号1から配列番号33からなる群から選択されるヌクレオチド配列を含む、前記インターロイキン12の35kDaサブユニット(IL12-p35)に方向づけされた、請求項35に記載の化合物。
- 配列番号34から配列番号85からなる群から選択されるヌクレオチド配列を含む、前記インターロイキン12の40kDaサブユニット(IL12-p40)に方向づけされた、請求項35に記載の化合物。
- 請求項35に記載の1つまたは複数のsiNAを含む製薬組成物。
- 直腸内投与用に配合された、請求項39に記載の組成物。
- RNA干渉を引き起こす化合物を含み、直腸内投与用に配合された、腸疾患の治療のための製薬組成物。
- ex vivoでの細胞または組織において、IL12-p40及び/またはIL12-p35の発現を阻害する方法であって、請求項35から38のいずれか一項に記載の化合物で前記細胞または組織を処理する工程を含み、それによってIL12-p40及び/またはIL12-p35の発現が阻害される方法。
- 患者において、IL12-p40及び/またはIL12-p35の発現を阻害する方法であって、請求項35から38のいずれか一項に記載の化合物で前記患者を処理する工程を含み、それによってIL12-p40及び/またはIL12-p35の発現が阻害される方法。
- IL12-p40及び/またはIL12-p35に関連する疾患または症状の治療のための薬剤の製造における、請求項35から38のいずれか一項に記載の化合物の使用であって、前記薬剤がIL12-p40及び/またはIL12-p35の発現を阻害する使用。
- 前記疾患が自己免疫疾患または炎症性腸疾患(IBD)である、請求項44に記載の使用。
- 前記疾患が多発性硬化症、糖尿病、またはクローン病である、請求項45に記載の使用。
- RNA干渉のための、腸組織を特異的に標的とする方法であって、直腸内にRNA干渉を引き起こす化合物を患者へ投与する工程を含む方法。
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US20130274317A1 (en) | 2010-11-04 | 2013-10-17 | Sandra Milena Ocampo | Derivatives of small interfering rnas and use thereof |
WO2013028771A1 (en) | 2011-08-23 | 2013-02-28 | Leong Hwei Xian | Reversing intestinal inflammation by inhibiting retinoic acid metabolism |
US20150250474A1 (en) | 2014-03-04 | 2015-09-10 | Maquet Cardiovascular Llc | Surgical implant and method and instrument for installing the same |
US10499908B2 (en) | 2014-03-04 | 2019-12-10 | Maquet Cardiovascular Llc | Surgical implant and method and instrument for installing the same |
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US8067577B2 (en) | 2011-11-29 |
RU2007138031A (ru) | 2009-04-20 |
CA2599220C (en) | 2018-05-22 |
US20080249048A1 (en) | 2008-10-09 |
ES2587252T3 (es) | 2016-10-21 |
JP5756441B2 (ja) | 2015-07-29 |
EP2386298A1 (en) | 2011-11-16 |
BRPI0609323A2 (pt) | 2010-03-16 |
US20100317720A1 (en) | 2010-12-16 |
WO2006097768A2 (en) | 2006-09-21 |
JP2008532540A (ja) | 2008-08-21 |
US20110313016A1 (en) | 2011-12-22 |
CN101184480A (zh) | 2008-05-21 |
WO2006097768A3 (en) | 2007-03-29 |
AU2006224338A1 (en) | 2006-09-21 |
CN103432592A (zh) | 2013-12-11 |
CA2599220A1 (en) | 2006-09-21 |
AU2006224338B2 (en) | 2011-01-06 |
EP2386298B1 (en) | 2016-07-06 |
RU2418594C2 (ru) | 2011-05-20 |
MX2007011235A (es) | 2007-11-14 |
GB0505081D0 (en) | 2005-04-20 |
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