JP5907866B2 - ダウン症候群遺伝子に対する天然アンチセンス転写物の抑制によるダウン症候群遺伝子関連疾患の治療 - Google Patents
ダウン症候群遺伝子に対する天然アンチセンス転写物の抑制によるダウン症候群遺伝子関連疾患の治療 Download PDFInfo
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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。
dancing feet syndrome);ダンディ・ウォーカー症候群;ドーソン病(Dawson disease);ド・モルシェ症候群(De Morsier‘s syndrome);デジェリーヌ・クルンプケ麻痺(Dejerine-Klumke palsy);認知症;皮膚筋炎;糖尿病性神経障害;広汎性硬化症;自律神経障害;書字障害;失読症;ジストニア;早期乳児てんかん性脳症;エンプティセラ症候群;脳炎;脳ヘルニア;脳三叉神経領域血管腫症;てんかん;エルブ麻痺;本態性振戦症;ファブリー病;ファール症候群;失神;家族性痙性麻痺;熱性痙攣;フィッシャー症候群;フリードライヒ失調症;前頭側頭型認知症および他の「タウオパチー」;ゴーシェ病;ゲルストマン症候群;巨細胞性動脈炎;巨細胞封入体病;グロボイド細胞白質ジストロフィー;ギラン・バレー症候群;HTLV-1関連脊髄症;ハラーホルデン・スパッツ病;頭部損傷;頭痛;片側顔面痙攣;遺伝性痙性対麻痺;多発神経炎型遺伝性運動失調症;耳帯状疱疹;帯状疱疹;ヒラヤマ症候群(Hirayama syndrome);HIV関連認知症およびHIV関連ニューロパチー(同様にAIDSの神経症状);全前脳症;ハンチントン病および他のポリグルタミン反復疾患(polyglutamine repeat disease);水無脳症;水頭症;副腎皮質ホルモン過剰症;低酸素症;免疫介在性脳脊髄炎;封入体筋炎;色素失調症;乳児フィタン酸蓄積症;乳児レフスム病;点頭てんかん;炎症性ミオパチー;頭蓋内嚢胞;頭蓋内圧亢進;ジュベール症候群;カーンズ・セイヤー症候群;ケネディ病;キンスボーン症候群(Kinsbourne syndrome);クリッペル・ファイル症候群;クラッベ病;クーゲルベルク・ヴェランダー病;クールー病;ラフォラ病;ランバート・イートン症候群;ランドウ・クレフナー症候群;延髄外側(ワレンベルグ)症候群;学習障害;リー病;レノックス・ガストー症候群;レッシュ・ナイハン症候群;白質ジストロフィー;レビー小体型認知症;脳回欠損;閉じ込め症候群;ルー・ゲーリック病(すなわち、運動ニューロン疾患または筋萎縮性側索硬化症);腰部椎間板症;ライム病-神経性後遺症;マシャド・ジョセフ病;巨大脳髄症;巨脳症;メルカーソン・ローゼンタール症候群;メニエール病;髄膜炎;メンケス病;異染性白質ジストロフィー;小頭症;片頭痛;ミラー・フィッシャー症候群;小発作;ミトコンドリア筋症;メビウス症候群;単肢筋萎縮症(monomelic amyotrophy);運動ニューロン疾患;もやもや病;ムコ多糖症;多発脳梗塞性認知症;多巣性運動ニューロパチー;多発性硬化症および他の脱髄障害;体位性低血圧症を伴う多系統萎縮症;進行性筋ジストロフィー;重症筋無力症;ミエリン破壊性広汎性硬化症(myelinoclastic diffuse sclerosis);乳児ミオクローヌス性脳症;ミオクローヌス;ミオパチー;先天性筋緊張症;ナルコレプシー;神経線維腫症;悪性症候群;AIDSの神経症状;狼瘡の神経性後遺症;神経性筋強直症;ニューロンセロイド脂褐素症;神経細胞移動障害;ニーマン・ピック病;オサリバン・マクラウド症候群(O‘Sullivan-McLeod syndrome);後頭神経痛;潜在性脊椎癒合不全の続発(occult spinal dysraphism sequence);大田原症候群;オリーブ橋小脳萎縮症;眼球クローヌス・ミオクローヌス;視神経炎;起立性低血圧症;オーバーユース症候群;感覚異常症;神経変性疾患または障害(パーキンソン病、ハンチントン病、アルツハイマー病、筋萎縮性側索硬化症(ALS)、認知症、多発性硬化症および神経細胞死に関連する他の疾患および障害);先天性パラミオトニア;腫瘍随伴疾患;発作;パリー・ロンベルク症候群;ペリツェウス・メルツバッヘル病;周期性四肢麻痺;末梢性ニューロパチー;有痛性ニューロパチーおよび神経因性疼痛;遷延性植物状態;広汎性発達障害;光くしゃみ反射;フィタン酸蓄積症;ピック病;神経圧迫(pinched nerve);下垂体腫瘍;多発性筋炎;孔脳症;ポリオ後症候群;ヘルペス後神経痛;麻疹後脳脊髄炎;体位性低血圧症;プラダー・ウィリー症候群;原発性側索硬化症;プリオン病;進行性顔面片側萎縮症;進行性多巣性白質脳症;進行性硬化性灰白異栄養(progressive sclerosing poliodystrophy);進行性核上性麻痺;偽脳腫瘍;ラムゼイ・ハント症候群(I型およびII型);ラスムッセン脳炎;反射性交感神経性ジストロフィー;レフサム病;反復運動障害(repetitive motion disorder);反復ストレス傷害;レストレスレッグス症候群;レトロウイルス関連脊髄症;レット症候群;ライ症候群;舞踏病;サンドホフ病;シルダー病;裂脳症;中隔視神経異形成症;揺さぶられっ子症候群;帯状疱疹;シャイ・ドレーガー症候群;シェーグレン症候群;睡眠時無呼吸;ソトス症候群;痙縮;二分脊椎症;脊髄損傷;脊髄腫瘍;脊髄性筋萎縮症;全身硬直症候群;脳卒中;スタージ・ウェーバー症候群;亜急性硬化性全脳炎;皮質下動脈硬化性脳症;シデナム舞踏病;失神;脊髄空洞症;遅発性ジスキネジア;テイ・サックス病;側頭動脈炎;脊髄係留症候群;トムゼン病;胸郭出口症候群;有痛性チック;トッド麻痺;トゥレット症候群;一過性脳虚血発作;伝達性海綿状脳症;横断性脊髄炎;外傷性脳損傷;振戦;三叉神経痛;熱帯性痙性不全対麻痺症;結節性硬化症;血管性認知症(多発脳梗塞性認知症);側頭動脈炎を含めた脈管炎;フォンヒッペル・リンダウ病;ワレンベルグ症候群;ウェルドニッヒ・ホフマン病;ウエスト症候群;むち打ち症;ウィリアムズ症候群;ウィルドン病;およびツェルウェガー症候群。
標的
一実施形態において標的は、限定することなく、ダウン症候群遺伝子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ダウン症候群遺伝子の核酸配列を含む。
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。
態をとる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。
ker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。
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。
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。
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。
ダウン症候群遺伝子ポリヌクレオチドおよび/またはダウン症候群遺伝子ポリヌクレオチドのセンス鎖に対してアンチセンスな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。
ダウン症候群遺伝子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)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(Applied Biosystems Inc.、Foster City CAによるApplied Biosystems Taqman Gene Expression Assay:Hs00176369_mlおよびHs00176369_ml)。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DYRK1a mRNAのレベルが、DYRK1aアンチセンスHs.713879(CUR-0885-CUR-0890)に対して設計されたオリゴのうちの1つでの処置の48時間後に有意に増大することを示す(図1)。
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-OH-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、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)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:Hs00176369_m1およびHs00176369_m1、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)またはStepOne Plus Real Time PCR Machine (Applied Biosystems)を使用。
Claims (28)
- in vivoまたはin vitroで患者の細胞または組織におけるダウン症候群遺伝子ポリヌクレオチドの発現を増大させるための医薬の製造における長さ12〜30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使用であって、
前記少なくとも1つのアンチセンスオリゴヌクレオチドが、配列番号7から13および21から23のいずれか一つに少なくとも90%の配列同一性を有し、かつ患者の細胞または組織においてダウン症候群遺伝子ポリヌクレオチドの発現を増大させる活性を有する使用。 - ダウン症候群遺伝子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に記載の使用。
- 少なくとも1つのアンチセンスオリゴヌクレオチドが、配列番号5または6から選択される配列を有するダウン症候群遺伝子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に記載の使用。
- 少なくとも1つのアンチセンスオリゴヌクレオチドがダウン症候群遺伝子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対して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に記載の使用。
- 少なくとも1つのアンチセンスオリゴヌクレオチドがダウン症候群遺伝子ポリヌクレオチドを有する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に記載の使用。
- 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に記載の使用。
- 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6に記載の使用。
- 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6に記載の使用。
- 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)、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6に記載の使用。
- 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つの配列番号16〜23に記載のオリゴヌクレオチド配列を含む、請求項1に記載の使用。
- in vivoまたはin vitroで哺乳動物の細胞または組織におけるダウン症候群遺伝子の発現を増大させるための医薬の製造における長さ19〜30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の使用であって、
前記少なくとも1つのsiRNAオリゴヌクレオチドが、ダウン症候群遺伝子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7から13および21から23のいずれか一つに少なくとも90%の配列同一性を有し、かつ哺乳動物の細胞または組織においてダウン症候群遺伝子ポリヌクレオチドの発現を増大させる活性を有する、使用。 - in vivoまたはin vitroで哺乳動物の細胞または組織におけるダウン症候群遺伝子の発現を増大させるための医薬の製造における、ダウン症候群遺伝子ポリヌクレオチドの天然アンチセンス鎖に特異的な長さ12〜30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使用であって、
前記少なくとも1つのアンチセンスオリゴヌクレオチドが、配列番号7から13および21から23のいずれか一つに少なくとも90%の配列同一性を有し、かつ哺乳動物の細胞または組織においてダウン症候群遺伝子ポリヌクレオチドの発現を増大させる活性を有する使用。 - 長さ12〜30ヌクレオチドの合成修飾オリゴヌクレオチドであって、配列番号5のヌクレオチド1〜497および配列番号6のヌクレオチド1〜545を有する天然アンチセンスポリヌクレオチド中の連続した12〜30ヌクレオチドを含むポリヌクレオチドの逆相補物に配列同一性を有し、少なくとも1つの修飾をさらに含み、
前記少なくとも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、
前記天然アンチセンスポリヌクレオチドの領域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でダウン症候群遺伝子DSCR1の発現を増大させるアンチセンス化合物であり、配列番号7から13および21から23のいずれか一つに少なくとも90%の配列同一性を有し、かつ患者の細胞または組織においてダウン症候群遺伝子ポリヌクレオチドの発現を増大させる活性を有す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13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13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13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)、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13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13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)、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13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13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13に記載のオリゴヌクレオチド。
- 前記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in vivoまたはin vitroで少なくとも1つのダウン症候群遺伝子ポリヌクレオチドの発現を増大させる、請求項13に記載のオリゴヌクレオチド。
- 配列番号16〜23に記載の配列を含む、請求項13に記載のオリゴヌクレオチド。
- 1つまたは複数の請求項13に記載のオリゴヌクレオチド及び薬学的に許容される賦形剤を含む組成物。
- オリゴヌクレオチドが、1つまたは複数の修飾または置換を含む、請求項24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25に記載の組成物。
- 少なくとも1つのダウン症候群遺伝子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医薬の製造における少なくとも1つの請求項13に記載のオリゴヌクレオチドの使用であって、
前記少なくとも1つのオリゴヌクレオチドが、前記少なくとも1つのダウン症候群遺伝子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つのダウン症候群遺伝子ポリヌクレオチドの発現を増大させる使用。 - 少なくとも1つのダウン症候群遺伝子ポリヌクレオチドに関連する疾患が、癌から選択されるDSCR1の突然変異体、異常な発現または機能に関連する疾患または障害から選択される、請求項27に記載の使用。
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EP2446037A4 (en) | 2013-11-06 |
EP2446037B1 (en) | 2016-04-20 |
US10876117B2 (en) | 2020-12-29 |
CN102482672A (zh) | 2012-05-30 |
US20120142758A1 (en) | 2012-06-07 |
CA2765815A1 (en) | 2010-12-29 |
US8921330B2 (en) | 2014-12-30 |
US10036014B2 (en) | 2018-07-31 |
US20200032263A1 (en) | 2020-01-30 |
KR20120086282A (ko) | 2012-08-02 |
US10450567B2 (en) | 2019-10-22 |
US20150073040A1 (en) | 2015-03-12 |
CN102482672B (zh) | 2016-11-09 |
EP2446037A2 (en) | 2012-05-02 |
WO2010151674A3 (en) | 2011-07-21 |
JP2012531427A (ja) | 2012-12-10 |
ES2583691T3 (es) | 2016-09-21 |
WO2010151674A2 (en) | 2010-12-29 |
US20180305693A1 (en) | 2018-10-25 |
KR101807324B1 (ko) | 2017-12-08 |
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