JP2012517244A - グリア細胞由来神経栄養因子(gdnf)関連疾病の、gdnfに対する天然アンチセンス転写物の抑制による治療 - Google Patents
グリア細胞由来神経栄養因子(gdnf)関連疾病の、gdnfに対する天然アンチセンス転写物の抑制による治療 Download PDFInfo
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Abstract
Description
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:一実施形態において標的は、限定されることなく、GDNFに関連するセンスおよび/またはアンチセンスの非コードおよび/またはコード配列を含めた、グリア細胞由来神経栄養因子(GDNF)の核酸配列を含む。
異常、アルコールまたは薬物乱用(例えば、エクスタシー、メタンフェタミンなど)により生じる神経毒性、精神遅滞または認知障害(例えば、非症候性X連鎖精神発達遅滞、脆弱性X症候群、ダウン症、自閉症)、失語症、ベルまひ(顔面神経まひ)、クロイツフェルト・ヤコブ病、脳炎、加齢に伴う黄斑変性症、オンディーヌ症候群、WAGR症候群、難聴、ウェルドニッヒ・ホフマン病、慢性近位型脊髄性筋萎縮症、ギラン・バレー症候群、多系統萎縮症(シャイ・ドレーガー症候群)、レット症候群、てんかん、脊髄損傷、脳卒中、低酸素症、虚血症、脳障害、糖尿病性神経障害、腎疾患または腎機能不全、末梢神経障害、神経移植合併症、運動ニューロン疾患、末梢神経障害、肥満、メタボリック・シンドローム、癌、湿疹、腸運動障害、ヒルシュスプルング病、アカラシア、食道けいれん、強皮症(食道の平滑筋部分の筋萎縮症、食道体部の下3分の2の収縮低下、及び低部食道括約筋不全関連性、さらには免疫抑制剤による治療により引き起こされるもの)、十二指腸潰瘍、ゾリンジャー・エリソン症候群、胃酸分泌過多、吸収不良疾患、表皮性及び間質性創傷治癒障害及び/または瘢痕性障害、進行性筋萎縮症(例えば、デュシェーヌ型、ベッカー型、エメリ・ドレフュス(Emery-Dreifuss)型、ランドゥジー-デジュリーヌ型、肩甲上腕、肢帯、フォングレーフェ‐フックス(Von Graefe Fuch)型、眼咽頭筋、筋緊張性及び先天性)、先天性または後天性筋疾患、貧血(大赤血球性貧血及び再生不良性貧血を含む);血小板減少症;形成不全;播種性血管内凝固症候群(DIC);骨髄異形成;免疫性(自己免疫性)血小板減少性紫斑病(ITP)、HIV誘発性ITP、血小板の疾患、ウイルス感染、神経系腫瘍疾病もしくは疾患、神経免疫疾病もしくは疾患、及び神経耳鼻科的疾病もしくは疾患、蝸牛感覚細胞損傷、聴覚不全、褐色細胞腫、多発性内分泌腺腫2型、フォン・ヒッペル・リンドウ病(VHL)、神経線維腫症1型;及び、加齢及び老化に伴う疾病もしくは疾病が含まれる。
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、(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、挿入剤、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。
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EC50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。
グリア細胞由来神経栄養因子(GDNF)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。
GDNFポリヌクレオチドの調節
アンチセンスオリゴヌクレオチドでのHUVEC細胞の処置
ATCC (Promo Cell cat# C-12253)由来のHUVEC細胞を上皮増殖培地(Promo Cell cat #C-22010)中、37℃、5% CO2で増殖させた。実験前日に、Promo Cell Detach Kit (cat# C-41200)を用いて、細胞を1.5×105個/ml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な上皮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、HUVEC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導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、培地を新鮮な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によって設計されたプライマー/プローブ(Applied Biosystems Inc., Foster City CAによるApplied Biosystems Taqman Gene Expression Assays: Hs01931883_s1)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、StepOne Plus Real Time PCR Machine (Applied Biosystems Inc.)またはMx4000 thermal cycler (Stratagene)を使用。
ABIアッセイID 76009981
フォワードプライマー: GCAGGACTACTACTGTGGTTATGAC (配列番号35)
リバースプライマー: CCACCCCCAGAATTATCCCTCTA (配列番号36)
プローブ (FAM): TCAAGCGCAAAGTTAC (配列番号37)
フォワードプライマー: GCCGGCTGTCGTGTTTC (配列番号.: 38)
リバースプライマー: AGCAAGGAGGCGGAACG (配列番号.: 39)
プローブ (FAM): CTTCCTGCCGGTAATC (配列番号.: 40)
ABI アッセイID Hs01931883_s1
コンテキスト配列(Context sequence): CATGTTGCAGACCCATCGCCTTTGA (配列番号.: 41)
リアルタイムPCR結果は、HUVEC細胞中のGDNF mRNAのレベルが、GDNF アンチセンスA(CUR-0117、P=0.02)及びPR(CUR-0121、P=0.05、CUR-0122、P=0.01)に対して設計された完全にホスホチオエート化された主鎖(骨格、backbone)を有する2つのオリゴでの処置の48時間後に有意に増大することを示す(図1A)。同じ試料においてGDNFアンチセンスAのレベルはCUR-0117での処置後に有意に低下したことを示す(図1B)。
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導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)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によって設計されたプライマー/プローブ(Applied Biosystems Inc., Foster City CAによるApplied Biosystems Taqman Gene Expression Assays: Hs01931883_s1)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、StepOne Plus Real Time PCR Machine (Applied Biosystems)を使用。
リアルタイムPCR結果は、HepG2細胞中のGDNF mRNAのレベルが、GDNFアンチセンスBX505687に対して設計された完全にホスホチオエート化された主鎖での処置の48時間後に有意に増大したことを示す(図1C)。
ATCC (cat# CRL-1587)由来のVero76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1.5×105個/ml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ウエルプレート中の培地を新鮮な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水で濃度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、Vero76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導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、培地を新鮮な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によって設計されたプライマー/プローブ(Applied Biosystems Inc., Foster City CAによるApplied Biosystems Taqman Gene Expression Assays: Hs01931883_s1)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、StepOne Plus Real Time PCR Machine (Applied Biosystems)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導入試料との間での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、Vero細胞中のGDNF mRNAのレベルが、GDNFアンチセンスBX505687に対するアンチセンスオリゴヌクレオチドでの処置の48時間後に有意に増大したことを示す(図1D)。
ATCC (cat# CRL-2273)由来のCHP212細胞を増殖培地(MEM/F12 (ATCC cat# 30-2003及びMediatech cat # 10-080-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、CHP212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導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)またはHigh Capacity cDNA Reverse Transcription Kit(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 Taqman Gene Expression Assay: Hs01931883_s1、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、StepOne Plus Real Time PCR Machine (Applied Biosystems)を使用。
リアルタイムPCR結果は、CHP212細胞中のGDNF mRNAのレベルが、GDNFアンチセンスに対して設計された3つのオリゴでの処置の48時間後に有意に増大したことを示す(図1E)。
GDNFアンチセンス転写物特異的オリゴヌクレオチドの霊長類への送達
全ての実験を、NIHガイドライン及び制度的な動物ケア承認に従って行う。MRIガイダンスの下、それぞれの猿に、尾状核、被核(putamen)及び黒質中の両側に(bilaterally)、本発明のアンチセンスオリゴヌクレオチド組成物を6つの定位置で注入(injection)投与する。注入を、尾状核の先端(10マイクロリットル)、尾状核(5マイクロリットル)、前部被核(10マイクロリットル)、交連被核(commissural putamen)(10マイクロリットル)、交連後被核(postcommissural putamen)(5マイクロリットル)、及び黒質(5マイクロリットル)の主部(body)中に行う。注入を、0.5マイクロリットル/分の速度でポンプに接続されている10マイクロリットルのHamiltonシリンジを通して行う。注入の間、対象とする標的へのオリゴヌクレオチド組成物のより良い分散のために、針を1から2mm持ち上げる。針をさらに3分間所定の位置に置いて、針先からの注入液の拡散を可能にする。左側部位には右側部位の6週間前に注入する。
パーキンソニズムに関して猿モデルを治療するためのGDNFのアンチセンスオリゴヌクレオチドの使用
猿での実験的なパーキンソニズムを神経毒であるMPTP(1-メチル-4-フェニル-1,2,3,6 テトラヒドロピリジン)を投与することにより作製し、該動物を本発明のアンチセンスオリゴヌクレオチドで処理して疾病の症状の発現を阻害する。
Claims (37)
- in vivoまたはin vitroで患者の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの機能および/または発現を調節する方法であって、
配列番号2のヌクレオチド1〜237または配列番号3のヌクレオチド1〜1246または配列番号4のヌクレオチド1〜684(図3)、または配列番号42のヌクレオチド1〜400または配列番号43のヌクレオチド1〜619または配列番号44のヌクレオチド1〜813中の約5〜約30の連続するヌクレオチドを含むポリヌクレオチドの逆相補物に少なくとも50%の配列同一性を有する長さ約5から約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に、前記細胞または組織を接触させるステップ;及び
それによりin vivoまたはin vitroで患者の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの機能および/または発現を調節するステップ
を含む方法。 - in vivoまたはin vitroで患者の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの機能および/または発現を調節する方法であって、
グリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの天然アンチセンスの逆相補物に少なくとも50%の配列同一性を有する長さ約5〜約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に、前記細胞または組織を接触させるステップ;及び
それによりin vivoまたはin vitroで患者の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの機能および/または発現を調節するステップ
を含む方法。 - in vivoまたはin vitroで患者の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの機能および/または発現を調節する方法であって、
グリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドに対するアンチセンスオリゴヌクレオチドに少なくとも50%の配列同一性を有する長さ約5〜約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に、前記細胞または組織を接触させるステップ;及び
それによりin vivoまたはin vitroで患者の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの機能および/または発現を調節するステップ
を含む方法。 - in vivoまたはin vitroで患者の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの機能および/または発現を調節する方法であって、グリア細胞由来神経栄養因子(GDNF)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の領域を標的にする少なくとも1つのアンチセンスオリゴヌクレオチドに、前記細胞または組織を接触させるステップ;及び
それによりin vivoまたはin vitroで患者の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの機能および/または発現を調節するステップ
を含む方法。 - グリア細胞由来神経栄養因子(GDNF)の機能および/または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4に記載の方法。
- 少なくとも1つのアンチセンスオリゴヌクレオチドがグリア細胞由来神経栄養因子(GDNF)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4に記載の方法。
- 少なくとも1つのアンチセンスオリゴヌクレオチドがグリア細胞由来神経栄養因子(GDNF)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を含む核酸配列を標的にする、請求項4に記載の方法。
- 少なくとも1つのアンチセンスオリゴヌクレオチドがグリア細胞由来神経栄養因子(GDNF)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標的にする、請求項4に記載の方法。
- 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み合わせから選択される1つまたは複数の修飾を含む、請求項4に記載の方法。
- 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み合わ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9に記載の方法。
- 1つまたは複数の修飾がホスホロチオエート、2'-O-メトキシエチル(MOE)、2'-フルオロ、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み合わ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9に記載の方法。
- 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)、それらの類似体、誘導体および組み合わ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9に記載の方法。
- 少なくとも1つのオリゴヌクレオチドが配列番号5〜34に記載のオリゴヌクレオチド配列の少なくとも1つを含む、請求項1に記載の方法。
- in vivoまたはin vitroで哺乳動物の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)遺伝子の機能および/または発現を調節する方法であって、
グリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドのアンチセンスおよび/またはセンス核酸分子の少なくとも約5個の連続する核酸の相補配列に少なくとも50%の配列同一性を有する、グリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドのアンチセンスポリヌクレオチドに特異的な、長さ約5〜約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に、前記細胞または組織を接触させるステップ;及び
in vivoまたはin vitroで哺乳動物の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)の機能および/または発現を調節するステップ
を含む方法。 - 前記オリゴヌクレオチドが、グリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドのアンチセンスおよび/またはセンス核酸分子に相補的な少なくとも約5個の連続する核酸の配列に少なくとも80%の配列同一性を有する、請求項14に記載の方法。
- in vivoまたはin vitroで哺乳動物の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)の機能および/または発現を調節する方法であって、
配列番号1から4に記載の少なくとも1つの核酸配列に少なくとも50%の配列同一性を有する、グリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドのセンスおよび/または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、長さ約5〜約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に、前記細胞または組織を接触させるステップ;及び
in vivoまたはin vitroで哺乳動物の細胞または組織におけるグリア細胞由来神経栄養因子(GDNF)の機能および/または発現を調節するステップ
を含む方法。 - 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、およびそれらの組み合わせから選択され、正常対照と比較してin vivoまたはin vitroでグリア細胞由来神経栄養因子(GDNF)遺伝子にハイブリダイズし、かつグリア細胞由来神経栄養因子(GDNF)遺伝子の機能および/または発現を調節す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み合わ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17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17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主鎖を含む、請求項17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、およびそれらの組み合わ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17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、およびそれらの組み合わせから選択される改変ヌクレオチドを含む複数の修飾を含む、請求項17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、およびそれらの組み合わ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17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、およびそれらの組み合わ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17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、およびそれらの組み合わ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17に記載のオリゴヌクレオチド。
- 長さ少なくとも約5〜約30ヌクレオチドのオリゴヌクレオチドであり、グリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドのアンチセンス鎖および/またはセンス鎖にハイブリダイズし、グリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドのアンチセンスおよび/またはセンスのコードおよび/または非コード核酸配列の少なくとも約5個の連続する核酸の相補配列に少なくとも約20%の配列同一性を有する、請求項17に記載のオリゴヌクレオチド。
- グリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドのアンチセンスおよび/またはセンスのコードおよび/または非コード核酸配列の少なくとも約5個の連続する核酸の相補配列に少なくとも約80%配列同一である、請求項17に記載のオリゴヌクレオチド。
- 少なくとも1つのグリア細胞由来神経栄養因子(GDNF)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in vivoまたはin vitroで少なくとも1つのグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの発現および/または機能を調節する、請求項17に記載のオリゴヌクレオチド。
- 配列番号5〜34に記載の配列の少なくとも1つを含む、請求項17に記載のオリゴヌクレオチド。
- アンチセンス配列、相補配列、対立遺伝子、相同体、アイソフォーム、変種、誘導体、変異体、断片またはそれらの組み合わせを含む、1つまたは複数のグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドに特異的な1つまたは複数のオリゴヌクレオチドを含む組成物。
- 1つまたは複数のオリゴヌクレオチドが、配列番号5〜34に記載のヌクレオチド配列のいずれか1つと比較して少なくとも約40%の配列同一性を有する、請求項30に記載の組成物。
- 1つまたは複数のオリゴヌクレオチドの少なくとも1つが、配列番号5〜34に記載のヌクレオチド配列を含む、請求項30に記載の組成物。
- 配列番号5〜34に記載のオリゴヌクレオチドが、1つまたは複数の修飾または置換を含む、請求項32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み合わせから選択される、請求項33に記載の組成物。
- 少なくとも1つのグリア細胞由来神経栄養因子(GDNF)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方法であって、
前記少なくとも1つのグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの天然アンチセンス配列に結合し、かつ前記少なくとも1つのグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドの発現を調節する少なくとも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患者に投与し;それにより少なくとも1つのグリア細胞由来神経栄養因子(GDNF)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ステップ
を含む方法。 - 少なくとも1つのグリア細胞由来神経栄養因子(GDNF)ポリヌクレオチドに関連する疾患が、神経再生不良に関連する疾病または疾患;神経変性疾病もしくは疾患(例えば、アルツハイマー病、パーキンソン病、ハンチントン病、筋萎縮性側索硬化症など)、精神神経疾患(うつ病、統合失調症、統合失調症様疾患、統合失調性感情障害、及び妄想性障害;パニック障害、(広場恐怖症を含む)恐怖症、強迫神経症、心的外傷後ストレス、双極性障害、神経性無食欲症、神経性大食症などの不安障害、中枢神経系の自己免疫疾患(例えば、多発性硬化症)、記憶喪失、長期または短期記憶障害、良性健忘症、幼児期学習障害(childhood learning disorder)、閉鎖性頭部外傷、注意欠陥障害、ウイルス感染への神経反応、脳障害、ナルコレプシー、睡眠障害(例えば、概日リズム障害、不眠症とナルコレプシー);神経断裂または神経損傷、脳脊髄神経索(CNS)の断裂、及び脳もしくは神経細胞への損傷、AIDSに関連する神経学的欠損、運動及び/もしくは声帯チックによって特徴付けられる運動性チック障害(例えば、トゥレット障害、慢性運動もしくは声帯チック障害、一過性チック障害、及び常同運動障害)、薬物乱用障害(例えば、薬物依存、薬物乱用、及び、薬物誘発性精神的疾患、薬物禁断症状及び薬物誘発性認知症などの薬物乱用/依存の後遺症、または健忘障害)、外傷性脳障害、耳鳴り、神経痛(例えば、三叉神経痛)、疼痛(例えば、慢性痛、慢性炎症性疼痛、関節炎関連疼痛、繊維筋痛、背痛、癌関連疼痛、消化器疾患関連疼痛、クローン病関連疼痛、自己免疫性疾患関連疼痛、内分泌疾患関連疼痛、糖尿病性神経障害関連疼痛、幻肢痛、自発性疼痛、慢性術後疼痛、慢性顎関節疼痛、灼熱痛、ヘルペス後神経痛、AIDS関連疼痛、複合性局所疼痛症候群I型及びII型、三叉神経痛、慢性背痛、脊髄損傷関連疼痛、薬物摂取関連疼痛及び再発性急性疼痛、神経因性疼痛)、異常神経活動により生じる、糖尿病、MS及び運動ニューロン疾患、運動失調、筋硬直(痙性)、顎関節機能不全、報酬欠乏症候群(RDS)などの疾病における神経性感覚異常、アルコールまたは薬物乱用(例えば、エクスタシー、メタンフェタミンなど)により生じる神経毒性、精神遅滞または認知障害(例えば、非症候性X連鎖精神発達遅滞、脆弱性X症候群、ダウン症
、自閉症)、失語症、ベルまひ(顔面神経まひ)、クロイツフェルト・ヤコブ病、脳炎、加齢に伴う黄斑変性症、オンディーヌ症候群、WAGR症候群、難聴、ウェルドニッヒ・ホフマン病、慢性近位型脊髄性筋萎縮症、ギラン・バレー症候群、多系統萎縮症(シャイ・ドレーガー症候群)、レット症候群、てんかん、脊髄損傷、脳卒中、低酸素症、虚血症、脳障害、糖尿病性神経障害、腎疾患または腎機能不全、末梢神経障害、神経移植合併症、運動ニューロン疾患、末梢神経障害、肥満、メタボリック・シンドローム、癌、湿疹、腸運動障害、ヒルシュスプルング病、アカラシア、食道けいれん、強皮症(食道の平滑筋部分の筋萎縮症、食道体部の下3分の2の収縮低下、及び低部食道括約筋不全関連性、さらには免疫抑制剤による治療により引き起こされるもの)、十二指腸潰瘍、ゾリンジャー・エリソン症候群、胃酸分泌過多、吸収不良疾患、表皮性及び間質性創傷治癒障害及び/または瘢痕性障害、進行性筋萎縮症(例えば、デュシェーヌ型、ベッカー型、エメリ・ドレフュス(Emery-Dreifuss)型、ランドゥジー-デジュリーヌ型、肩甲上腕、肢帯、フォングレーフェ‐フックス(Von Graefe Fuch)型、眼咽頭筋、筋緊張性及び先天性)、先天性または後天性筋疾患、貧血(大赤血球性貧血及び再生不良性貧血を含む);血小板減少症;形成不全;播種性血管内凝固症候群(DIC);骨髄異形成;免疫性(自己免疫性)血小板減少性紫斑病(ITP)、HIV誘発性ITP、血小板の疾患、ウイルス感染、神経系腫瘍疾病もしくは疾患、神経免疫疾病もしくは疾患、及び神経耳鼻科的疾病もしくは疾患、蝸牛感覚細胞損傷、聴覚不全、褐色細胞腫、多発性内分泌腺腫2型、フォン・ヒッペル・リンドウ病(VHL)、神経線維腫症1型;及び、加齢及び老化に伴う疾病もしくは疾病から選択される、請求項35に記載の方法。 - In vivo投与のために少なくとも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、病態に関連する標的ポリヌクレオチドを選択するステップ;選択された標的ポリヌクレオチドまたは選択された標的ポリヌクレオチドに対するアンチセンスであるポリヌクレオチドに相補的である少なくとも5個の連続するヌクレオチドを含む少なくとも1つのアンチセンス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、標的ポリヌクレオチドもしくは選択された標的ポリヌクレオチドに対するアンチセンスであるポリヌクレオチドとアンチセンスオリゴ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;及び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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2010
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WO2010093906A2 (en) | 2010-08-19 |
WO2010093906A3 (en) | 2011-04-07 |
JP2016192977A (ja) | 2016-11-17 |
CN102439149B (zh) | 2018-01-02 |
US20200291407A1 (en) | 2020-09-17 |
CN102439149A (zh) | 2012-05-02 |
JP6813304B2 (ja) | 2021-01-13 |
CA2752239A1 (en) | 2010-08-19 |
KR20110121696A (ko) | 2011-11-08 |
JP6066035B2 (ja) | 2017-01-25 |
EP2396408A4 (en) | 2013-06-19 |
CA2752239C (en) | 2021-03-30 |
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ES2658626T3 (es) | 2018-03-12 |
US20110319476A1 (en) | 2011-12-29 |
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