JP6128846B2 - パラオキソナーゼ(pon1)に対する天然アンチセンス転写物の抑制によるpon1遺伝子関連疾患の治療 - Google Patents
パラオキソナーゼ(pon1)に対する天然アンチセンス転写物の抑制によるpon1遺伝子関連疾患の治療 Download PDFInfo
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- JP6128846B2 JP6128846B2 JP2012516233A JP2012516233A JP6128846B2 JP 6128846 B2 JP6128846 B2 JP 6128846B2 JP 2012516233 A JP2012516233 A JP 2012516233A JP 2012516233 A JP2012516233 A JP 2012516233A JP 6128846 B2 JP6128846 B2 JP 6128846B2
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- oligonucleotide
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- paraoxonase
- polynucleotide
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Description
本出願は、それぞれ参照によりその全体が本明細書に組み込まれる2009年6月16日出願米国仮特許出願第61/187,311号の優先権を主張する。
本発明の実施形態は、PON1遺伝子および関連する分子の発現および/または機能を調節するオリゴヌクレオチドを含む。
配列番号1:ヒト(Homo sapiens)パラオキソナーゼ1(PON1)、mRNA (NCBI受託番号:NM_000446)
配列番号2:天然PON1アンチセンス配列(Hs.611732)。
配列番号3〜7:アンチセンスオリゴヌクレオチド。*はホスホチオエート結合を示す。
本明細書において使用される専門用語は、特定の実施形態を記載する目的のためだけであり、本発明の限定となることを意図しない。本明細書において使用される単数形「a」、「an」および「the」は、文脈がそうでないと明確に示さなければ複数形を同様に含んで意味する。さらに用語「含んでいる(including)」、「含む(include)」、「有している(having)」、「有する(has)」、「有する(with)」またはそれらの変形は、詳細な記載および/または特許請求の範囲のいずれにおいても使用され、そのような用語は用語「含む(comprising)」と同様の様式で包括的であることを意図する。
標的:ある態様において、標的は、パラオキソナーゼ1 (PON1)に関するセンスおよび/またはアンチセンスノンコーディングおよび/またはコーディング配列を、制限なく含む、パラオキソナーゼ1 (PON1)の核酸配列を含む。
重鎖形成領域)は、ワトソン-クリック様に塩基対形成する相補的RNA鎖である。
態を取る1本鎖から形成される場合、2本鎖(または1本鎖の2重鎖形成領域)は、ワトソン-クリック様に塩基対形成する自己相補的RNA鎖である。
飾は、De Mesmaekerら(1995)、Acc. Chem. Res.、28:366〜374に見出すことができる。
外来性核酸の宿主細胞または生体への輸送は、細胞中または生体中の核酸を直接検出するステップによって評価されうる。そのような検出は、当技術分野において周知のいくつかの方法によって達成されうる。例えば、外来性核酸の存在は、サザンブロットまたは核酸に関連するヌクレオチド配列を特異的に増幅するプライマーを使用するポリメラーゼ連鎖反応(PCR)技術によって検出されうる。外来性核酸の発現も遺伝子発現分析を含む従来法を使用して測定されうる。例えば外来性核酸から産生されるmRNAはノーザンブロットおよび逆転写PCR(RT-PCR)を使用して検出および定量されうる。
本発明の化合物は、診断、治療および予防のためにならびに研究用試薬およびキットの構成要素として利用されうる。さらに、精緻な特異性を有して遺伝子発現を抑制できるアンチセンスオリゴヌクレオチドは、当業者によって特定の遺伝子の機能を解明するため、または生物学的経路の種々のメンバー間の機能を区別するためにしばしば使用される。
本発明のオリゴヌクレオチドの他の修飾は、オリゴヌクレオチドの活性、細胞分布または細胞への取込みを増強する1つまたは複数の成分または複合体のオリゴヌクレオチドへの化学的連結を含む。これらの成分または複合体は、1級または2級ヒドロキシル基などの官能基に共有結合した複合基を含みうる。本発明の複合基は、干渉物質、レポーター分子、ポリアミン、ポリアミド、ポリエチレングリコール、ポリエーテル、オリゴマーの薬力学特性を増強する基、およびオリゴマーの薬物動態特性を増強する基を含む。典型的な複合基は、コレステロール、脂質、リン脂質、ビオチン、フェナジン、葉酸、フェナントリジン、アントラキノン、アクリジン、フルオレセイン、ローダミン、クマリン、および色素を含む。本発明の文脈において薬力学特性を増強する基は、取込みを改善し、分解への耐性を増強し、および/または標的核酸との配列特異的ハイブリダイゼーションを強化する基を含む。本発明の文脈において薬物動態特性を増強する基は、本発明の化合物の取込み、分布、代謝または排出を改善する基を含む。代表的複合基は、参照により本明細書に組み込まれる1992年10月23日出願の国際特許出願PCT/US92/09196および米国特許第6,287,860号において開示されている。複合体成分は、これだけに限らないがコレステロール成分、コール酸、チオエーテル、例えばヘキシル-S-トリチルチオール、チオコレステロール、脂肪族鎖、例えばドデカンジオールまたはウンデシル残基、リン脂質、例えばジ-ヘキサデシル-rac-グリセロールまたはトリエチルアンモニウム1,2-ジ-O-ヘキサデシル-rac-グリセロ-3-H-ホスホネート、ポリアミンまたはポリエチレングリコール鎖、あるいはアダマンタン酢酸、パルミチル成分、またはオクタデシルアミンもしくはヘキシルアミノ-カルボニル-オキシコレステロール成分などの脂質成分を含む。本発明のオリゴヌクレオチドは、活性原薬、例えばアスピリン、ワルファリン、フェニルブタゾン、イブプロフェン、スプロフェン、フェンブフェン、ケトプロフェン、(S)-(+)-プラノプロフェン、カプロフェン、ダンシルサルコシン、2,3,5-トリヨード安息香酸、フルフェナム酸、フォリン酸、ベンゾチアジアジド、クロロチアジド、ジアセピン、インドメチシン、バルビツール酸、セファ
ロスポリン、サルファ剤、抗糖尿病薬、抗菌剤または抗生物質とも複合体化されうる。
本発明の化合物は、取込み、分布および/または吸収の補助のために、例えばリポソーム、受容体-標的分子、経口、直腸、局所または他の製剤として、他の分子、分子構造または化合物と、混合物と混合、封入、複合体化または他の方法で付随されうる。そのような取込み、分布および/または吸収を補助する製剤の調製を説明する代表的米国特許は、これだけに限らないが、それぞれが本明細書に参照として組み込まれる米国特許5,108,921;5,354,844;5,416,016;5,459,127;5,521,291;5,543,165;5,547,932;5,583,020;5,591,721;4,426,330;4,534,899;5,013,556;5,108,921;5,213,804;5,227,170;5,264,221;5,356,633;5,395,619;5,416,016;5,417,978;5,462,854;5,469,854;5,512,295;5,527,528;5,534,259;5,543,152;5,556,948;5,580,575;および5,595,756を含む。
物は、一緒にまたは連続的に使用されうる。
治療用組成物の処方およびそれらの続く投与(投薬)は、当業者の技能の範囲内であると考えられる。投薬は、数日間から数カ月間続くまたは治療が効果的になるもしくは病態の減退が達成されるまでの治療過程において、治療される病態の重症度および応答性に依存する。最適な投薬計画は、患者身体での薬剤蓄積の測定から算出されうる。当業者は、最適投与量、投薬方法および繰り返し率(repetition rate)を容易に決定できる。最適な投与量は、個々のオリゴヌクレオチドの相対的効力に応じて変動する場合があり、一般にin vitroおよびin vivo動物モデルにおいて効果的であると見出されたEC50sに基づいて概算されうる。一般に投与量は、体重1kgあたり0.01μg〜100gであり、1日に、1週間に、1カ月にもしくは1年に1回もしくは複数回またはさらに2〜20年ごとに1回である場合がある。当業者は、測定された滞留時間および体液または組織における薬剤の濃度に基づいて投薬についての繰り返し率を容易に概算できる。治療の成功に続いて、病態の再発を予防するために患者に維持療法を受けさせることが望ましい場合があり、ここでオリゴヌクレオチドは維持投与において体重1kgあたり0.01μg〜100g、1日1回または複数回から20年ごとに1回の範囲で投与される。
以下の非限定的実施例は、本発明の選択された実施形態を例示するために利用できる。示される構成要素の割合における変動および構成要素における代替は当業者に明らかであり、本発明の実施形態の範囲内であることは理解される。
パラオキソナーゼ(PON1)ポリヌクレオチドのアンチセンス鎖および/またはセンス鎖核酸分子に特異的なアンチセンスオリゴヌクレオチドの設計
上に示すとおり用語「に特異的なオリゴヌクレオチド」または「オリゴヌクレオチド標的」は、(i)標的遺伝子の一部分と安定な複合体を形成できる配列、または(ii)標的遺伝子のmRNA転写物の一部分と安定な2重鎖を形成できる配列を有するオリゴヌクレオチドを意味する。
PON1ポリヌクレオチドの調節
ATCC (cat# HB-8065)から得た518A2細胞を増殖培地(MEM/EBSS (Hyclone cat #SH30024またはMediatech cat # MT-10-010-CV) +10% FBS (Mediatech cat# MT35-011-CV)+ペニシリン/ストレプトマイシン(Mediatech cat# MT30-002-CI))中、37℃、5% CO2で増殖させた。実験前日に、細胞を1mlあたり1.5×105個の密度で6ウエルプレートに再播種し、37℃、5% CO2でインキュベートした。実験当日に6ウエルプレートの培地を新鮮増殖培地に交換した。全てのアンチセンスオリゴヌクレオチドを濃度20μMに希釈した。この溶液2μlをOpti-MEM培地(Gibco cat#31985-070) 400μlおよびLipofectamine 2000 (Invitrogen cat# 11668019) 4μlと室温で20分間インキュベートし、HepG2細胞を含む6ウエルプレートの各ウエルに添加した。オリゴヌクレオチド溶液の代わりに水2μlを含む同様の混合物を偽形質移入対照用に使用した。37℃、5% CO2での3〜18時間のインキュベーション後、培地を新鮮増殖培地に交換した。アンチセンスオリゴヌクレオチドの添加の48時間後、培地を除去し、RNAを細胞からPromegaからのSV Total RNA Isolation System (cat # Z3105)またはQiagenからのRNeasy Total RNA Isolationキット(cat# 74181)を製造者の手順書に従って使用して抽出した。RNA 600ngをThermo ScientificからのVerso cDNAキット(cat#AB1453B)またはHigh Capacity cDNA Reverse Transcriptionキットcat# 4368813)を製造者の手順書に記載のとおり使用して実施した逆転写反応に加えた。この逆転写反応からのcDNAをABI Taqman Gene Expression Mix (cat#4369510)およびABI (Applied Biosystems Inc.、Foster City CAによるApplied Biosystems Taqman Gene Expression Assay)によって設計されたプライマー/プローブを使用するリアルタイムPCRによって遺伝子発現をモニターするために使用した。以下のPCRサイクルを使用した: 50℃で2分間、95℃で10分間、(95℃で15秒間、60℃で1分間)を40サイクル、Mx4000 thermal cycler (Stratagene)を使用。
リアルタイムPCR結果は、HepG2細胞中のPON1 mRNAのレベルが、PON1アンチセンスHs.158149およびHs.674841に対して設計されたアンチセンスオリゴでの処置の48時間後に有意に増加していることを示す(図1)。
Claims (25)
- in vivoまたはin vitroで患者の細胞または組織におけるパラオキソナーゼ1(PON1)ポリヌクレオチドの発現を増大させるための組成物であって、
配列番号3に少なくとも90%の配列同一性を有し、かつ、患者の細胞または組織におけるパラオキソナーゼ1(PON1)ポリヌクレオチドの発現を増大させる活性を有する長さ21〜30ヌクレオチドの少なくとも1つのアンチセンスオリゴヌクレオチドを含む組成物。 - パラオキソナーゼ1(PON1)の発現が、対照と比較してin vivoまたはin vitroで増大する、請求項1に記載の組成物。
- 少なくとも1つのアンチセンスオリゴヌクレオチドが、パラオキソナーゼ1(PON1)ポリヌクレオチドのコードおよび/または非コード核酸配列にアンチセンスである天然アンチセンスポリヌクレオチドを標的にする、請求項1に記載の組成物。
- 少なくとも1つのアンチセンスオリゴヌクレオチドが、パラオキソナーゼ1(PON1)ポリヌクレオチドに対しオーバーラップおよび/または非オーバーラップ配列を有する天然アンチセンスポリヌクレオチドを標的にする、請求項1に記載の組成物。
- 少なくとも1つのアンチセンスオリゴヌクレオチドが、少なくとも1つの修飾された糖部分、少なくとも1つの修飾されたヌクレオシド間結合、少なくとも1つの修飾されたヌクレオチド、およびそれらの組合せから選択される1つまたは複数の修飾を含む、請求項1に記載の組成物。
- 1つまたは複数の修飾が、2'-O-メトキシエチル修飾糖部分、2'-メトキシ修飾糖部分、2'-O-アルキル修飾糖部分、二環性糖部分、およびそれらの組合せから選択される少なくとも1つの修飾された糖部分を含む、請求項5に記載の組成物。
- 1つまたは複数の修飾が、ホスホロチオエート、アルキルホスホネート、ホスホロジチオエート、アルキルホスホノチオエート、ホスホラミデート、カルバミン酸、炭酸、リン酸トリエステル、アセトアミデート、カルボキシメチルエステル、およびそれらの組合せから選択される少なくとも1つの修飾されたヌクレオシド間結合を含む、請求項5に記載の組成物。
- 1つまたは複数の修飾が、ペプチド核酸(PNA)、ロックド核酸(LNA)、アラビノ核酸(FANA)、類似体、誘導体、およびそれらの組合せから選択される少なくとも1つの修飾されたヌクレオチドを含む、請求項5に記載の組成物。
- in vivoまたはin vitroで哺乳動物の細胞または組織におけるパラオキソナーゼ1(PON1)遺伝子の発現を増大させるための組成物であって、
配列番号2の配列を有するパラオキソナーゼ1(PON1)ポリヌクレオチドの天然アンチセンスポリヌクレオチドに特異的であり、配列番号3と少なくとも90%同一性を有し、かつ、哺乳動物の細胞または組織におけるパラオキソナーゼ1(PON1)ポリヌクレオチドの発現を増大させる活性を有する、長さ21〜30ヌクレオチドの少なくとも1つの低分子干渉RNA(siRNA)オリゴヌクレオチドを含む組成物。 - in vivoまたはin vitroで哺乳動物の細胞または組織におけるパラオキソナーゼ1(PON1)の発現を増大させるための組成物であって、
配列番号3に少なくとも90%の配列同一性を有し、哺乳動物の細胞または組織におけるパラオキソナーゼ1(PON1)ポリヌクレオチドの発現を増大させる活性を有する、パラオキソナーゼ1(PON1)ポリヌクレオチドの天然アンチセンス鎖の非コードおよび/またはコード配列に特異的な、長さ21〜30ヌクレオチドの少なくとも1つのアンチセンスオリゴヌクレオチドを含む組成物。 - 配列番号3に少なくとも90%の配列同一性を有する、少なくとも1つの修飾を含む合成修飾オリゴヌクレオチドであって、少なくとも1つの修飾が、少なくとも1つの修飾された糖部分、少なくとも1つの修飾されたヌクレオチド間結合、少なくとも1つの修飾されたヌクレオチド、およびそれらの組合せから選択され、天然アンチセンスオリゴヌクレオチドにハイブリダイズし、かつ正常対照と比較してin vivoまたはin vitroでパラオキソナーゼ1(PON1)遺伝子の発現を増大させるアンチセンス化合物であるオリゴヌクレオチド。
- 少なくとも1つの修飾が、ホスホロチオエート、アルキルホスホネート、ホスホロジチオエート、アルキルホスホノチオエート、ホスホラミデート、カルバミン酸、炭酸、リン酸トリエステル、アセトアミデート、カルボキシメチルエステル、およびそれらの組合せからなる群から選択されるヌクレオチド間結合を含む、請求項11に記載のオリゴヌクレオチド。
- 少なくとも1つのホスホロチオエートヌクレオチド間結合を含む、請求項11に記載のオリゴヌクレオチド。
- ホスホロチオエートヌクレオチド間結合の骨格を含む、請求項11に記載のオリゴヌクレオチド。
- ペプチド核酸、ロックド核酸(LNA)、類似体、誘導体、およびそれらの組合せから選択される少なくとも1つの修飾されたヌクレオチドを含む、請求項11に記載のオリゴヌクレオチド。
- ホスホロチオエート、アルキルホスホネート、ホスホロジチオエート、アルキルホスホノチオエート、ホスホラミデート、カルバミン酸、炭酸、リン酸トリエステル、アセトアミデート、カルボキシメチルエステル、およびそれらの組合せから選択される修飾されたヌクレオチドを含む複数の修飾を含む、請求項11に記載のオリゴヌクレオチド。
- ペプチド核酸、ロックド核酸(LNA)、類似体、誘導体、およびそれらの組合せから選択される修飾されたヌクレオチドを含む複数の修飾を含む、請求項11に記載のオリゴヌクレオチド。
- 2'-O-メトキシエチル修飾糖部分、2'-メトキシ修飾糖部分、2'-O-アルキル修飾糖部分、二環性糖部分、およびそれらの組合せから選択される少なくとも1つの修飾された糖部分を含む、請求項11に記載のオリゴヌクレオチド。
- 2'-O-メトキシエチル修飾糖部分、2'-メトキシ修飾糖部分、2'-O-アルキル修飾糖部分、二環性糖部分、およびそれらの組合せから選択される修飾された糖部分を含む複数の修飾を含む、請求項11に記載のオリゴヌクレオチド。
- 配列番号3に少なくとも90%の配列同一性を有し、患者の細胞または組織におけるパラオキソナーゼ1(PON1)ポリヌクレオチドの発現を増大させる活性を有する、1つまたは複数のオリゴヌクレオチド、ならびに薬学的に許容可能な賦形剤を含む組成物。
- 1つまたは複数の修飾または置換を含む、請求項20に記載の組成物。
- 1つまたは複数の修飾が、ホスホロチオエート、メチルホスホネート、ペプチド核酸、ロックド核酸(LNA)分子およびそれらの組合せから選択される、請求項21に記載の組成物。
- 配列番号2の配列を有する少なくとも1つのパラオキソナーゼ1(PON1)ポリヌクレオチドおよび/または少なくとも1つのそのコード産物に関連する疾患を予防するまたは治療するための組成物であって、
前記配列番号2の配列を有する少なくとも1つのパラオキソナーゼ1(PON1)ポリヌクレオチドの天然アンチセンス配列に結合し、配列番号3と少なくとも90%配列同一性を有し、かつ前記少なくとも1つのパラオキソナーゼ1(PON1)ポリヌクレオチドの発現を増大させる、長さ21〜30ヌクレオチドの少なくとも1つのアンチセンスオリゴヌクレオチドの治療有効量を含む組成物。 - 少なくとも1つのパラオキソナーゼ1(PON1)ポリヌクレオチドに関連する疾患が、心血管疾患または心血管障害、糖尿病、肥満、及び高コレステロール血症を含む代謝疾患または代謝障害、高血圧、アテローム性動脈硬化症、アテローム発生性の疾患または障害、冠動脈心疾患、酸化ストレス、神経疾患または神経障害、自閉症/自閉症スペクトラム障害、てんかん、癌、炎症、脳卒中、外傷、腎疾患、関節リウマチ、魚眼病、紫斑病、多嚢胞性卵巣症候群、甲状腺機能亢進症、肝疾患、血管性認知症、急性相反応の間の感染症を含む感染症、コバルト、カドミウム、ニッケル、亜鉛、銅、バリウム、ランタン、および水銀を含む金属;ジクロロ酢酸、ならびに四塩化炭素を含む環境化学物質、ならびにコリン作動性ムスカリン性アンタゴニスト、プラバスタチン、シンバスタチン、フルバスタチン、及びアルコールを含む薬物を含む種々の外因性化合物への曝露によって誘導されるストレス;加齢および老化から選択される、請求項23に記載の組成物。
- PON1ポリヌクレオチドの発現を増大させるためのin vivo投与のための少なくとも1つのオリゴヌクレオチドを同定および選択する方法であって、配列番号2の配列を有する、PON1ポリヌクレオチドの天然アンチセンスオリゴヌクレオチドを標的とする、少なくとも21個のヌクレオチドを含む少なくとも1つのオリゴヌクレオチドを同定するステップ;ストリンジェントなハイブリダイゼーション条件下における、アンチセンスオリゴヌクレオチドとPON1ポリヌクレオチドの天然アンチセンスオリゴヌクレオチドまたはPON1ポリヌクレオチドの天然アンチセンスオリゴヌクレオチドに対してアンチセンスであるポリヌクレオチドとのハイブリッドの熱的融点を測定するステップ;ならびに得られた情報に基づいてin vivo投与のための少なくとも1つのオリゴヌクレオチドを選択するステップ
を含む方法。
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