JP6128732B2 - アポリポタンパク質−a1に対する天然アンチセンス転写物の抑制によるアポリポタンパク質−a1関連疾患の治療 - Google Patents
アポリポタンパク質−a1に対する天然アンチセンス転写物の抑制によるアポリポタンパク質−a1関連疾患の治療 Download PDFInfo
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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2008年10月3日出願米国仮特許出願第61/102,681号、2009年2月12日出願米国仮特許出願第61/152,236号および2009年5月7日出願米国仮特許出願第61/176,267号の優先権を主張する。
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。
高密度リポタンパク質(HDL)は、血中の余分なコレステロールを取り上げ、肝臓に戻す。低密度リポタンパク質(またはLDL)は、身体でのコレステロールの主な輸送体である。しかし数年間にわたって過剰なLDLはアテローム性動脈硬化症(動脈の狭窄および硬化)をもたらし、心疾患または心臓発作に至る。比は、HDLコレステロール値をLDLコレステロール値で割ることによって決定される。例えば50mg/dLのHDLコレステロールおよび150mg/dLのLDLコレステロールを有する人の場合、HDL/LDL比は、0.33である。理想的なHDL/LDL比は0.4より上であり、目標は0.3より上のHDL/LDL比を維持することである。
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。
飾は、De Mesmaekerら、Acc. Chem. Res. 1995、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り込みを増強する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、取り込みを改善し、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り込み、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、取り込み、分布および/または吸収の補助ために、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。そのような取り込み、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。
アポリポタンパク質(ApoA1)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。
ApoA1ポリヌクレオチドの調節
材料と方法
細胞を以下の方法のいずれかで処置した。
ATCC (cat# HB-8065)由来のHepG2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0.5×104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1ウエルあたり1.5mlの新鮮増殖培地で置換した。
全てのアンチセンスオリゴヌクレオチドを水で濃度20μMまで希釈した。この溶液2μlを新鮮増殖培地400μlと混合し、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処置対照用に使用した。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72時間後、細胞に上に記載のとおり再投薬した。2回目の投薬の48〜72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 kit (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)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 (18Sについてcat# 4319413E、ApoA1についてHs00163641_ml、Applied Biosystems Inc.、Foster City CA)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。アンチセンスオリゴヌクレオチドでの処置後の遺伝子発現における倍数変化を処置試料と偽処置試料との間での18S-標準化dCt値の差に基づいて算出した。
ATCC (cat# HB-8065)由来のHepG2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 kit (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)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 (18Sについてcat# 4319413E、ApoA1についてHs00163641_ml、Applied Biosystems Inc.、Foster City CA)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。アンチセンスオリゴヌクレオチドでの処置後の遺伝子発現における倍数変化を処置試料と偽形質移入試料との間での18S-標準化dCt値の差に基づいて算出した。
リアルタイムPCR結果は、HepG2細胞中のApoA1 mRNAのレベルが、ApoA1アンチセンスDA327409extへのアンチセンスオリゴヌクレオチドでの処置の48時間後にHepG2細胞において有意に増加していることを示す(図1)。
ApoA1遺伝子発現の調節
材料および方法
細胞を以下の方法のいずれかで処置した。
HepG2細胞をMEM/EBSS (Hyclone cat #SH30024) +10%FBS+ペニシリン+ストレプトマイシン中、37℃、5%CO2で増殖させた。実験前日に、細胞を1mlあたり1.5×104個の密度で6ウエルプレートに再播種し、37℃、5%CO2に置いた。実験当日に6ウエルプレートの培地を新鮮MEM/EBSS+10%FBSに交換した。IDTによって製造された全てのアンチセンスオリゴヌクレオチドを濃度20μMまで希釈した。この溶液2μlをOpti-MEM media (Gibco cat#31985-070) 400μlとインキュベートし、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。アンチセンスオリゴヌクレオチドの添加の72時間後に培地を除去し、上に記載のとおり投薬手順を繰り返した。
反復投薬の48〜72時間後、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 kit(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)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 (18Sについてcat# 4319413E、ApoA1についてHs00163641_ml、およびApoA1アンチセンスDA327409extについて特注設計されたアッセイ、全てApplied Biosystems Inc.、Foster City CAによる)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。
アンチセンスオリゴヌクレオチドでの処置後の遺伝子発現における倍数変化を処置試料と偽形質移入試料との間での18S-標準化dCt値の差に基づいて算出した。
ApoA1天然アンチセンスDA327409extについて特注設計されたTaqmanアッセイ用のプライマーおよびプローブ。大文字は未修飾デオキシリボヌクレオチドを示す。
順方向プライマー配列CTCCTCCTGCCACTTCTTCTG (配列番号163)
逆方向プライマー配列CTGGTGGATGAAGAAGGTTTGC (配列番号164)
プローブ配列(FAM標識) TTTGGATCTGGACGACTTC (配列番号165)
ATCC (cat# HB-8065)由来のHepG2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))、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 kit (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)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 (18Sについてcat# 4319413E、ApoA1についてHs00163641_ml、およびApoA1アンチセンスDA327409extについて特注設計されたアッセイ、全てApplied Biosystems Inc.、Foster City CAによる)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。アンチセンスオリゴヌクレオチドでの処置後の遺伝子発現における倍数変化を処置試料と偽形質移入試料との間での18S-標準化dCt値の差に基づいて算出した。
ApoA1天然アンチセンスDA327409extについて特注設計されたTaqmanアッセイ用のプライマーおよびプローブ。大文字は未修飾デオキシリボヌクレオチドを示す。
順方向プライマー配列CTCCTCCTGCCACTTCTTCTG (配列番号163)
逆方向プライマー配列CTGGTGGATGAAGAAGGTTTGC (配列番号164)
プローブ配列(FAM標識) TTTGGATCTGGACGACTTC (配列番号165)
RNA 600ngをThermo ScientificからのVerso cDNAキット(cat#AB1453B)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 (18Sについてcat# 4319413E、ApoA1についてHs00163641_ml、およびApoA1アンチセンスDA327409extについて特注設計されたアッセイ、全てApplied Biosystems Inc.、Foster City CA)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。アンチセンスオリゴヌクレオチドでの処置後の遺伝子発現における倍数変化を処置試料と偽形質移入試料との間での18S-標準化dCt値の差に基づいて算出した。
ELISAは、MabTech Inc. ApoA1 ELISA kit cat# 3710-11-6を製造者の手順書に従って使用して実施した。
アフリカミドリザルにおけるCUR-962の作用の効果および持続時間の研究
本研究の目的は、APOA1遺伝子を制御する不調和性非コードアンチセンス配列のアンチセンスノックダウンの効果を非ヒト霊長類モデルでの静脈投与に続いて評価および比較することであった。APOA1制御配列を抑制するために設計したアンチセンスオリゴヌクレオチド被験物質をCUR-962と記す。
CUR-962: +G*+C*T*A*G*T*C*T*G*+T*+T*+G (配列番号170)
CUR-963 (対照): +G*+T*C*T*G*A*T*G*G*+A*+G*+A (配列番号171)
この研究は、承認された毒物学的原理に従い、調和国際会議(International Conference of Harmonization)(ICH)の3者間で調和されたガイドライン(Harmonized Tripartite Guidelines)(医薬品の臨床試験のための非臨床試験の実施時期についてICH M3(m)、2000年9月)および治療薬の検査に関して一般に認められた手順に従って設計した。
被験物質同一性および調製
被験物質CUR-962は、化学的に安定化されたアンチセンスオリゴヌクレオチドである。静脈内送達のためのビヒクルはリン酸緩衝食塩水(PBS)である。
PBSビヒクル、組成物、バッチ番号、有効期限および保存条件(温度および明/暗)については供給者から得た。
被験物質およびビヒクルはスポンサーおよび製造者によって提供された標準とされる保存条件に従って保存した。
被験物質製剤の試料は濃度、安定性および検査物質製剤の均一性の分析のために凍結保存する。
霊長類は、規制当局に潜在的危険性の指標として許容され、詳細な背景データが入手可能である適切な非げっし類種である。具体的にはアフリカミドリザルは、ヒトの多数の生理学的状態および病態に関して高く臨床的に関連するモデルである。
種
ミドリザル(Chlorocebus sabaeus)、非ヒト霊長類
品種
アフリカミドリザルSt. Kitts原産
RxGen、Lower Bourryeau、St. Kitts、West Indies
実験動物は成体であった。
サル体重およそ3〜4kg。実際の範囲は、変動する場合があるがデータに記載される。
実験動物は成体メスであった。
動物10匹を研究への登録に適する動物8匹の同定を保証するために選別した。
メス:8匹
この研究は、アフリカミドリザルにおける被験物質の治療効果を評価する主な目的とこの種でのこの種類のオリゴヌクレオチドの全身投与の先行研究とが両立する、可能な限り少ない数の動物を使用して設計した。
体重範囲3〜4kgのアフリカミドリザル成体10匹を研究に使用した。サルは、島に生息する野生集団から人道的に捕獲した薬剤未投与の成体動物である。捕獲されたサルは、可能性があるいなかる腸内寄生虫負担をも排除するために駆虫薬で処置し、研究登録のための選別に先行する最短4週間、検疫で観察した。捕獲したサルの年齢は大きさおよび歯状形によって、研究から高齢の動物を排除して推定した。研究登録に先行して、自発運動および敏捷さの評価を含む臨床検査を各サルに実施した。血液試料を採取し、Antech Diagnostics (Memphis、TN)に包括的臨床化学ならびに全血球計算および脂質プロファイルのために送った(詳細は9.2節および319567928を参照されたい)。St. Kittsコロニーのサルについて確立された正常値と比較して異常な検査値であると決定されたサルは、研究から排除した。この判定基準を満たす8匹のサルを同定するために、必要に応じて追加的動物の選別を伴って10匹のサルを選別した。研究開始前に、選択されたサルを1週間個別収容に慣らすために個別のケージに移す。実験に適するとみなされた動物だけを研究に登録する。研究開始時の実際の(または推定の)年齢および体重範囲は、生データおよび最終報告に詳述する。
最高水準の動物福祉に従い、the St. Kitts Department of Agricultureおよび米国保健社会福祉省によって定められたガイドラインを遵守した。全ての研究は、これらの要件および実験動物の管理および収容に関して適用される全ての行動基準に従って実施される。動物の管理および使用についてのNIHガイドラインに含まれるとおりの獣医医療、手術および検査に関する全ての適用される基準。St. Kitts施設は、指針に定められたとおり手順書を検査し、施設を監査する動物実験委員会を有している。財団は、指針#A4384-01 (Axion Research Foundation/St. Kitts Biomedical Foundation)に定められたとおり実験動物福祉部門に申請された保証を承認している。特別な非ヒト霊長類獣医学的な管理問題およびこの研究に特化される調査によって生じるバイオハザード問題はない。
治療に関連するいかなる臨床症状の検出も可能にするために、動物は手術の前および手術後に屠殺されるまで個々に収容した。個々のケージが位置している霊長類ビルは、間接照明で全体が照らされており、北緯17°で、U.S. D.H.H.Sガイドラインにおいて推奨されるとおりおよそ12時間:12時間の明-暗周期であった。RxGen霊長類ビルを外部と十分に換気した。1年を通じてSt. Kittsで典型的である一定の標的温度23〜35℃に維持するために追加的な気流を天井扇によって確実にした。温度および相対湿度(これも管理されない)の24時間での両極値を毎日測定した。研究中、ケージを定期的に清掃した。
各動物に1日当たりおよそ90グラムの標準的サル用固形飼料餌(TekLad, Madison, WI)を与えた。餌の詳細な栄養組成を記録した。水は、微生物学的な純度について定期的に分析した。保存餌および給水の中の混入物の許容されるレベルについての基準は、それぞれ餌製造者および定期的な施設水評価によって確立された分析仕様内であった。水は、ヒト用の消費に許容されるとする証明のために必要な全ての基準に合致した。
動物識別および無作為化
割り付けを体重および血漿コレステロールプロファイルに基づく層別無作為化の手段によって行った。群への割り付けの前後に、各動物を腹部への刺青によって識別した。刺青は、日常的健康診査の過程でコロニーの全動物に識別の手段として行われる。ケージ図を収容された個体を識別するために作成し、個々のサルをそれらそれぞれのケージに付けた標識タグによってさらに識別した。
各群サル4匹からなる2処置群に動物を割り当てた。特定の動物識別番号を施設番号付けシステムに従って各サルに付けた。このシステムは、文字に続く3桁の数字、例えばY032によって各サルを一意的に識別する。
動物に、1、3および5日目に1日1回、約10分間かけて手動輸液によって静脈内に送達して投薬した。点滴速度は、24mL/kg/時間である。動物は、投薬手順前および投薬手順中にケタミンおよびキシラジンによって鎮静させた。静脈カテーテル(Terumo mini vein infusion set、20ゲージ針、または同様の適切な輸液セット)を伏在血管に挿入した。各サルにおける投薬は、午前8時から10時の間、動物が起きた直後で摂食の前に実施した。血漿コレステロールおよび下の血液化学節に記載の他の脂質レベルを評価するための血液試料を各輸液の直前に採取した。コレステロール測定値への摂食の影響を最小化するために血液採取は両方の試料採取間隔で摂食に先行した。
処置への応答の全ての明らかな兆候を各投薬日に記録した。追加的に動物を少なくとも1週間に1回、外見および一般的状態などの身体的特性について検査した。
体重を治療中および治療後期に1週間ごとに記録した。
個々の摂餌量は定量しなかった。しかし摂食様式をモニターし、大きな変化は記録した。
死亡率と罹患率を記録する。早期屠殺に関するいかなる決定も可能であれば試験責任者とスポンサーのモニタリング科学者との協議の後に行われる。早期に死んでいるまたは殺されることがわかった動物は、病理組織診断のための肝臓、腎臓、心臓および脾臓肺組織の採取を伴う検死の対象になる。早期屠殺事象においては、血液試料を(可能であれば)採取し、パラメーターを測定する。通常の勤務時間後に死んでいることがわかった動物は、一晩冷凍され、次の勤務時間の開始時に検死を行う。動物の状態が早期屠殺を必要とする場合は、ペントバルビタールナトリウムの静脈内過剰投与によって安楽死させる。全ての調査は、動物の使用に関する原則によって管理される。RxGenは、穏やかと特定されたこの研究での手順が遵守しなければならない過酷さのレベルを指示する、霊長類施設に関する米国社会保健福祉省基準に従うことが法律によって定められている。
血液試料
3つの血液試料を血漿コレステロールベースラインを確立するために処置前に全ての動物から得た。血液試料は、処置後に採取し、浅静脈への穿刺を介して取った。いずれの試料採取時点でも採取した容量は、サル成体の総血液量のおよそ4%を表す8mlを超えなかった。
全血球数計算(CBC)、プロトロンビン時間、PTT、フィブリノーゲンおよびD-ダイマーを1、6および11日目に採取した全ての血液試料について測定した(これらの時点のいずれかで混乱が検出された場合は追加的な日にも)。血球計算は、EDTAを含むバキュテナーに採取された全血1mlについて評価した。凝集プロファイル決定は、クエン酸デキストロース(ACD)抗凝固剤を含むバキュテナーに採取された血液およそ2mlについて実施した。
グルコース、血液尿素窒素、クレアチニン、総タンパク質量、アルブミン、総ビリルビン量、アルカリホスファターゼ、アラニンアミノ基転移酵素(ALT)、アルパラギンアミノ基転移酵素(AST)、コレステロール、カルシウム、リン、ナトリウム、カリウム、塩素、A/G比、BUN/クレアチニン(計算)グロブリン(計算)、リパーゼ、アミラーゼ、トリグリセリド、CPK、乳酸脱水素酵素、ガンマグルタミン酸転移酵素(GGT)、マグネシウム、総コレステロールLDL、VLDL、HDL、ApoA1、ApoA2、ApoB、ApoE、ApoLp(a)。スーパー化学(Superchemistry)ならびにLDLおよびHDL測定を全ての血漿試料について行った。アポリポタンパク質測定をLDLおよびHDLデータの評価後に選択した試料について行った。
経皮的肝生検をベースライン時および7および17日目に全てのサルについて実施した。14ゲージ生検針(INRAD)を肝臓の右および左の両葉からコア生検2個(長さ約1.0cm)を得るために使用する。生検の成功は、細分前に下に詳述のとおり生検針上の生検試料の目視検査によって確認した。
統計学
血液学、臨床化学および脂質プロファイルについて記述統計学を実施した。適切な生物情報学分析を発現データについて実行した。
試料サイズ決定を、アフリカミドリザルに修飾されたアンチセンスオリゴヌクレオチドを投与し、臨床化学および脂質プロファイル変化および関連する多様性が得られた先行実験に基づいて行った。効能評価のための全対象数は、処置群あたり動物4匹で登録された動物20匹および追加選別動物4匹であった。
結果を以下の図に示す。図6:ApoA1 mRNA(上パネル)およびタンパク質(下パネル)レベルは、リアルタイムPCRおよびELISAによってそれぞれ決定されたとおりベースラインレベルと比較して、CUR-962(ApoA1アンチセンスDA327409extに対して設計したオリゴヌクレオチド)での処置後にサル肝生検で増加していた(左パネル2つ)。ApoA1 mRNAおよびタンパク質レベルは、in vitroでApoA1レベルに効果を示さないオリゴヌクレオチドを投薬された対照群の同じ期間後に変化しなかった(CUR-963、右パネル2つ)。
Claims (26)
- 患者の細胞または組織におけるアポリポタンパク質ApoA1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81、84、87、93、99から101、104、108から111、116、117、119、121から129、131、134、136、137、139、142、145、149、157、159、160、170、および173の塩基配列のいずれかに少なくとも90%の配列同一性を有し、患者の細胞または組織におけるアポリポタンパク質ApoA1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11〜30ヌクレオチドのオリゴヌクレオチドを含む組成物。 - アポリポタンパク質ApoA1の発現が対照と比較して増大する、請求項1に記載の組成物。
- オリゴヌクレオチドが、配列番号2を有するアポリポタンパク質ApoA1ポリヌクレオチドの天然アンチセンス配列を標的にする、請求項1に記載の組成物。
- オリゴヌクレオチドが、アポリポタンパク質ApoA1ポリヌクレオチドの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。
- オリゴヌクレオチドが、アポリポタンパク質ApoA1ポリヌクレオチドの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。
- オリゴヌクレオチドが、修飾された糖部分、修飾されたヌクレオシド間結合、修飾されたヌクレオチドおよび/またはそれらの組合せを含む1つまたは複数の修飾を含む、請求項1に記載の組成物。
- 修飾された糖部分が、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または二環性糖部分を含む、請求項6に記載の組成物。
- 修飾されたヌクレオシド間結合が、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/またはそれらの組合せを含む、請求項6に記載の組成物。
- オリゴヌクレオチドが、ペプチド核酸、ロックド核酸(LNA)分子、アラビノ-核酸(FANA)、ペプチド核酸(PNA)、それらの類似体または誘導体を含む少なくとも1つの修飾されたヌクレオチドを場合により有する、請求項6に記載の組成物。
- オリゴヌクレオチドがコア配列gctagt(配列番号172)を含む、請求項1に記載の組成物。
- 哺乳動物の細胞または組織におけるアポリポタンパク質ApoA1遺伝子の発現を増大させるための組成物であって、
アポリポタンパク質ApoA1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な長さ19〜30ヌクレオチドの低分子干渉RNA(siRNA)オリゴヌクレオチド
を含み、前記siRNAオリゴヌクレオチドの一本鎖が配列番号81、84、87、93、99から101、104、108から111、116、117、119、121から129、131、134、136、137、139、142、145、149、157、159、160、170、および173の塩基配列のいずれかに少なくとも90%の配列同一性を有し(ただしT(チミン)はU(ウラシル)に置き換えられており)、哺乳動物の細胞または組織におけるアポリポタンパク質ApoA1ポリヌクレオチドの発現を増大させる活性を有する、組成物。 - 前記siRNAオリゴヌクレオチドの一本鎖が、アポリポタンパク質ApoA1ポリヌクレオチドから転写されるRNAポリヌクレオチドの少なくとも19個の連続する核酸配列に少なくとも90%の配列同一性を有する、請求項11に記載の組成物。
- 哺乳動物の細胞または組織におけるアポリポタンパク質ApoA1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81、84、87、93、99から101、104、108から111、116、117、119、121から129、131、134、136、137、139、142、145、149、157、159、160、170、および173の塩基配列のいずれかに記載の少なくとも1つの核酸配列に少なくとも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アポリポタンパク質ApoA1ポリヌクレオチドの発現を増大させる活性を有する、アポリポタンパク質ApoA1分子をコードするポリヌクレオチドの天然アンチセンス鎖の配列に特異的な長さ11〜30ヌクレオチドのオリゴヌクレオチド
を含む組成物。 - 配列番号81、84、87、93、99から101、104、108から111、116、117、119、121から129、131、134、136、137、139、142、145、149、157、159、160、170、および173の塩基配列のいずれかに少なくとも90%の配列同一性を有し、患者の細胞または組織におけるアポリポタンパク質ApoA1ポリヌクレオチドの発現を増大させる活性を有し、少なくとも1つの修飾を含む、長さ11〜30ヌクレオチドの合成修飾オリゴヌクレオチドであって、修飾がアルキルホスホネート、ホスホロチオエート、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またはそれらの組合せのうちの少なくとも1つのヌクレオチド間結合を含み、アポリポタンパク質ApoA1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ハイブリダイズし、かつ正常対照と比較してアポリポタンパク質ApoA1分子の発現を増大させる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と、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/またはそれらの組合せからなる群から選択される少なくとも1つのヌクレオチド間結合との組合せを含む、請求項14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14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14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)分子、類似体、誘導体および/またはそれらの組合せを含む少なくとも1つの修飾されたヌクレオチドを場合により含む、請求項14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または二環性糖部分を含む修飾された糖部分を含む、請求項14に記載のオリゴヌクレオチド。
- アポリポタンパク質ApoA1ポリヌクレオチドから転写されるRNAポリヌクレオチドの少なくとも10個の連続する核酸に少なくとも90%配列同一である、請求項14に記載のオリゴヌクレオチド。
- 少なくとも1つのアポリポタンパク質ApoA1ポリ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少なくとも1つのアポリポタンパク質ApoA1ポリヌクレオチドの発現を増大させる、請求項14に記載のオリゴヌクレオチド。
- コア配列gctagt(配列番号172)を含む、請求項14に記載のオリゴヌクレオチド。
- 1つまたは複数の請求項14に記載のオリゴヌクレオチドと医薬的に許容可能な賦形剤とを含む組成物。
- オリゴヌクレオチドが1つまたは複数の修飾されたまたは置換されたヌクレオチドを含む、請求項23に記載の組成物。
- 修飾されたヌクレオチド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)分子を含む修飾された塩基を含む、請求項24に記載の組成物。
- 心血管障害を予防または治療するための組成物であって、
アポリポタンパク質ApoA1ポリヌクレオチドの天然アンチセンス配列に結合し、かつ前記アポリポタンパク質ApoA1ポリヌクレオチドの発現を増大させる、少なくとも1つの請求項14に記載のオリゴヌクレオチドの治療有効量を患者に投与することにより心血管障害を予防するまたは治療する、組成物。
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