JP2017061569A - 脳由来神経栄養因子(bdnf)関連疾病の、bdnf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
脳由来神経栄養因子(bdnf)関連疾病の、bdnf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
【解決手段】本発明は、また、これらのアンチセンスオリゴヌクレオチドの同定、及びBDNFの発現に関連する疾病及び疾患の治療におけるそれらの使用にも関する。
【選択図】なし
Description
本出願は、その出願が参照によりその全体が本明細書中に援用される、2009年2月12日に出願された米国仮特許出願第61/152,132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。
標的:一実施形態において、標的は、限定されることなく、BDNF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む、脳由来神経栄養因子(BDNF)の核酸配列を含む。
、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、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、視神経障害、糖尿病性神経障害、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、ぜんそく、アトピー性疾患、アレルギー性炎、湿疹、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、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。実施形態において、患者は、少なくとも約1、少なくとも約2、少なくとも約3、少なくとも約4、少なくとも約5、少なくとも約6、少なくとも約7、少なくとも約8、少なくとも約9、少なくとも約10、少なくとも約15、少なくとも約20、少なくとも約25、少なくとも約30、少なくとも約35、少なくとも約40、少なくとも約45、少なくとも約50、少なくとも約60、少なくとも約70、少なくとも約80、少なくとも約90、または少なくとも約100 mg/kg体重である薬物用量で処理される。アンチセンスオリゴヌクレオチドの特定の注射された用量は、例えば、米国特許第7,563,884号、「Antisense modulation of PTP1B expression」に記載され、その全体が参照により本明細書中に援用される。
脳由来神経栄養因子(BDNF)ポリヌクレオチドに対してアンチセンスとなる核酸分子および/または脳由来神経栄養因子(BDNF)ポリヌクレオチドのセンス鎖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。
BDNF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HepG2細胞の処置
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)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。
ABI アッセイID Hs00417345_m1
コンテキスト配列(context sequence) GCACACCTGGAGATACTCTATTATA (SEQ ID No.: 9)
ABIアッセイID Hs00542425_s1
CCTGCAGAATGGCCTGGAATTACAA (SEQ ID No.: 10)
リアルタイムPCR結果は、HepG2細胞中のBDNF mRNAのレベルが、BDNFアンチセンス(CUR-71, P=0.04、CUR-73, P=0.07、CUR-76, P=0.03)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を有する2つのLNAギャップマーでの処置の48時間後に有意に増大することを示す(図1A)。同一の試料において、BDNFアンチセンスのレベルがCUR-72を除く全てのオリゴで処理後に有意に減少したが、これは、恐らくはBDNF及び/またはBDNFアンチセンスの異なるスプライス変異体に影響を与える異なるオリゴのためである(図1B)。
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: Hs00542425_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BDNF mRNAのレベルが、BDNF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1C)。
アミロイド-トランスジェニックマウスにおける、BDNFポリヌクレオチド及びタンパク質産物のアンチセンス調節並びに記憶及び学習に関する効果
スウェーデン人とインド人(Indiana)のAPP変異の両方を有するヒトアミロイド前駆体タンパク質(APP)導入遺伝子を発現する、J20マウスに、BDNF-AS(例えば、配列番号3〜8により同定されるオリゴヌクレオチド)特異的なアンチセンスオリゴヌクレオチドを投与する。例えば、参照により本明細書中に援用される、Nagahara, et al., 2009, 「Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease」, Nature Medicine 15(3): 331-337に記載されるように、これらのマウスは、2〜3月齢で発症する、内嗅皮質における皮質プラーク及び細胞の進行性消失を示し、認知低下を6〜7ヶ月までに示す。尾静脈より4から7滴を回収することによって投薬の数日前に前処理血液試料を回収する。各アンチセンスオリゴヌクレオチドをPBS中に溶解させて、約10 mg/kgで、内嗅皮質または海馬中に注射によりマウスに投与する。対照群マウス(年齢を一致させたWT同腹子)に同量のPBS単独を投与する。1ヵ月後に、処理及び対照マウスにおいて空間記憶をモリス水迷路で試験し、それらの能力を比較する。海馬依存的及び海馬非依存的学習力を測定することにより回復効果もまた試験する。試験後、マウスを殺害し脳組織(内嗅皮質及び海馬歯状回)をBDNFのタンパク質及びmRNAの発現解析用に回収する。ヒトBDNFタンパク質濃度及び分泌レベルを、製造業者の指示に従って、酵素免疫蛍光測定(ELISA)キット(例えば、Quantikine human BDNF, R&D Systems, Minneapolis, MNより市販)を用いて決定する。本明細書のいずれかに記載されるように、RT-PCRを用いてmRNAをアッセイする。
SAM-P8マウスにおける、BDNFポリヌクレオチド及びタンパク質産物のアンチセンス調節並びに記憶及び学習に関する効果
例えば、参照により本明細書中に援用される、米国特許第6,310,048号, 「Antisense modulation of amyloid beta protein expression」に記載されるように、老化促進マウス(SAM)のP8系統は、学習(獲得)障害及び記憶(維持)障害の加齢に伴う増加並びにアミロイド前駆体タンパク質及びAβPの蓄積の加齢に伴う増加を示す。標準的なR1マウスの正常寿命が24ヶ月であるのとは対照的に、SAM-P8マウスは17.2ヶ月の平均寿命を有する。
筋萎縮性側索硬化症の患者における、BDNFポリヌクレオチド及びタンパク質産物のアンチセンス調節並びに疾病の進行に関する効果
本発明のアンチセンスオリゴヌクレオチド(例えば、配列番号3〜8のいずれかにより同定されるオリゴヌクレオチド)を含む製薬組成物を家族性ALSに罹患する個人の脳脊髄液に投与する。Medtronic SycroMed IIポンプを使用して組成物を脳脊髄液に送達する。製造業者の指示に従ってポンプを外科的に移植する。ポンプリザーバーに製薬組成物入りリン酸緩衝整理食塩水を充填する。製薬組成物を、脳脊髄液中に、8 mgから12 mg/日のアンチセンスオリゴヌクレオチドの注入を達成させる量で投与する。アンチセンスオリゴヌクレオチドを少なくとも28日間注入する。外科的に髄腔内に移植されたカテーテル中に薬剤をプログラムされた用量で送り込む。
Claims (37)
- in vivoまたはin vitroで患者の細胞または組織における脳由来神経栄養因子(BDNF)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1〜3175(図3)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5から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脳由来神経栄養因子(BDNF)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脳由来神経栄養因子(BDNF)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、
脳由来神経栄養因子(BDNF)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5〜30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脳由来神経栄養因子(BDNF)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脳由来神経栄養因子(BDNF)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、
脳由来神経栄養因子(BDNF)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5〜30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脳由来神経栄養因子(BDNF)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脳由来神経栄養因子(BDNF)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、脳由来神経栄養因子(BDNF)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脳由来神経栄養因子(BDNF)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。 - 脳由来神経栄養因子(BDNF)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脳由来神経栄養因子(BDNF)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脳由来神経栄養因子(BDNF)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脳由来神経栄養因子(BDNF)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3〜8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脳由来神経栄養因子(BDNF)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、
脳由来神経栄養因子(BDNF)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約50%の配列同一性を有する、脳由来神経栄養因子(BDNF)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脳由来神経栄養因子(BDNF)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、脳由来神経栄養因子(BDNF)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脳由来神経栄養因子(BDNF)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及び2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、脳由来神経栄養因子(BDNF)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脳由来神経栄養因子(BDNF)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で脳由来神経栄養因子(BDNF)遺伝子にハイブリダイズし、かつ脳由来神経栄養因子(BDNF)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、脳由来神経栄養因子(BDNF)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、脳由来神経栄養因子(BDNF)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。
- 脳由来神経栄養因子(BDNF)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つの脳由来神経栄養因子(BDNF)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つの脳由来神経栄養因子(BDNF)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3〜8に記載の配列を含む、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つまたは複数の脳由来神経栄養因子(BDNF)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3〜8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3〜8に記載のヌクレオチド配列の1つを含む、請求項30に記載の組成物。
- 配列番号3〜8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つの脳由来神経栄養因子(BDNF)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つの脳由来神経栄養因子(BDNF)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つの脳由来神経栄養因子(BDNF)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つの脳由来神経栄養因子(BDNF)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つの脳由来神経栄養因子(BDNF)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、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、視神経障害、糖尿病性神経障害、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、ぜんそく、アトピー性疾患、アレルギー性炎、湿疹、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、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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EP3009150B1 (en) | 2019-11-13 |
JP2019206564A (ja) | 2019-12-05 |
JP6072842B2 (ja) | 2017-02-01 |
CA2752237C (en) | 2020-03-24 |
DK2396038T3 (en) | 2016-02-01 |
CN102387817B (zh) | 2018-01-30 |
EP2396038A2 (en) | 2011-12-21 |
JP2015127337A (ja) | 2015-07-09 |
CA2752237A1 (en) | 2010-08-19 |
US20110319475A1 (en) | 2011-12-29 |
KR101682735B1 (ko) | 2016-12-06 |
KR20110132357A (ko) | 2011-12-07 |
PT2396038E (pt) | 2016-02-19 |
ES2560107T3 (es) | 2016-02-17 |
JP2012517481A (ja) | 2012-08-02 |
US10519448B2 (en) | 2019-12-31 |
US9074210B2 (en) | 2015-07-07 |
ES2762610T3 (es) | 2020-05-25 |
EP2396038A4 (en) | 2013-06-19 |
CN102387817A (zh) | 2012-03-21 |
EP2396038B1 (en) | 2015-10-21 |
WO2010093904A9 (en) | 2011-09-09 |
HUE026280T2 (en) | 2016-06-28 |
WO2010093904A2 (en) | 2010-08-19 |
EP3009150A1 (en) | 2016-04-20 |
US20160138023A1 (en) | 2016-05-19 |
HK1160773A1 (zh) | 2012-08-17 |
HK1221914A1 (zh) | 2017-06-16 |
WO2010093904A3 (en) | 2011-01-06 |
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