JP6407912B2 - ヘモグロビン(hbf/hbg)に対する天然アンチセンス転写物の抑制によるhbf/hbg関連疾患の治療 - Google Patents
ヘモグロビン(hbf/hbg)に対する天然アンチセンス転写物の抑制によるhbf/hbg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。
好ましい実施形態において、アンチセンスオリゴヌクレオチドは、異常なグロビン遺伝子の発現または機能に関連する疾患または障害を予防または治療するのに使用される。ガンマグロビン遺伝子(HBG1およびHBG2)は、正常では胎児の肝臓、脾臓、および骨髄において発現する。2本のガンマ鎖は、2本のアルファ鎖と併せて胎児ヘモグロビン(HbF)を構成するが、これは正常では出生時に成人ヘモグロビン(HbA)により置き換えられる。一部のベータサラセミアおよび関連状態において、ガンマ鎖の生成は成人期にも持続される。2種類のガンマ鎖は、残基136において異なり、G-ガンマ生成物(HBG2)においてはここでグリシンが見出され、A-ガンマ生成物(HBG1)においてはここでアラニンが見出される。出生時においては前者が主要である。ベータグロビンクラスター内における遺伝子の順序は、5'-イプシロン--ガンマ-G--ガンマ-A--デルタ--ベータ--3'である。
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。
グロビンポリヌクレオチドの調節
材料および方法
ACACTCGCTTCTGGAACGTCTGAGGTTATCAATAAGCTCCTAGTCCAGACGCCATGGGTCATTTCACAGAGGAGGACAAGGCTACTATCACAAGCCTGTGGGGCAAGGTGAATGTGGAAGATGCTGGAGGAGAAACCCTGGGAAGgtaggctctggtgaccaggacaagggagggaaggaaggaccctgtgcctggcaaaagtccaggtcgcttctcaggatttgtggcaccttctgactgtcaaactgttcttgtcaatctcacagGCTCCTGGTTGTCTACCCATGGACCCAGAGGTTCTTTGACAGCTTTGGCAACCTGTCCTCTGCCTCTGCCATCATGGGCAACCCCAAAGTCAAGGCACATGGCAAGAAGGTGCTGACTTCCTTGGGAGATGCCACAAAGCACCTGGATGATCTCAAGGGCACCTTTGCCCAGCTGAGTGAACTGCACTGTGACAAGCTGCATGTGGATCCTGAGAACTTCAAGgtgagtccaggagatgtttcagccctgttgcctttagtctcgaggcaacttagacaacggagtattgatctgagcacagcagggtgtgagctgtttgaagatactggggttgggggtgaagaaactgcagaggactaactgggctgagacccagtggtaatgttttagggcctaaggagtgcctctaaaaatctagatggacaattttgactttgagaaaagagaggtggaaatgaggaaaatgacttttctttattagattccagtagaaagaactttcatctttccctcatttttgttgttttaaaacatctatctggaggcaggacaagtatggtcgttaaaaagatgcaggcagaaggcatatattggctcagtcaaagtggggaactttggtggccaaacatacattgctaaggctattcctatatcagctggacacatataaaatgctgctaatgcttcattacaaacttatatcctttaattccagatgggggcaaagtatgtccaggggtgaggaacaattgaaacatttgggctggagtagattttgaaagtcagctctgtgtgtgtgtgtgtgtgtgcgcgcgcgcgtgtgtgtgtgtgtgtcagcgtgtgtttcttttaacgtcttcagcctacaacatacagggttcatggtggcaagaagatagcaagatttaaattatggccagtgactagtgcttgaaggggaacaactacctgcatttaatgggaaggcaaaatctcaggctttgagggaagttaacataggcttgattctgggtggaagcttggtgtgtagttatctggaggccaggctggagctctcagctcactatgggttcatctttattgtctcctttcatctcaacagCTCCTGGGAAATGTGCTGGTGACCGTTTTGGCAATCCATTTCGGCAAAGAATTCACCCCTGAGGTGCAGGCTTCCTGGCAGAAGATGGTGACTGCAGTGGCCAGTGCCCTGTCCTCCAGATACCACTGAGCTCACTGCCCATGATTCAGAGCTTTCAAGGATAGGCTTTATTCTGCAAGCAATACAAATAATAAATCTATTCTGCTGAGAGATCAC。
GATTTATTAT TTGTATTGCT TGCAGAATAA AGCCTATCCT TGAAAGCTCT 50
GAnTCATGGG CAGTGAGCTC AGTGGnATCT GGnGGnCAGG GCACTGGCCA 100
CTGCAGTCAC CATCTTCTGC CAGGgnGCCT GCACCTCAGG GGTGAnTTCT 150
TTGCCGAAnT GGnTTGCCAA AnCGGTCACC AGCACATTTC CCAGGggCTT 200
GAAGTTCTCA GGnTCCACAT GCAGCTTGTC ACAGTGCAGT TCACTCAGCT 250
GGGCAAAGGT GCCnTTGAGA TCATCCgGGn GCTTTGTGGg nTCTCCCnAG 300
GgnGTCAGnA CCTTCTTGCC ATGTGCCTTG nCTTTGGGGg TTGCCCctgn 350
tgggcag。
HBF Hs.702397_3:
5'-rGrUrC rArArG rGrCrA rCrArU rGrGrC rArArG rArArG rGrUrG rCrUrG-3'
5'-rGrCrA rCrCrU rUrCrU rUrGrC rCrArU rGrUrG rCrCrU rUrGA C-3'
HBF Hs.702397_2:
5'-rCrCrU rGrGrC rArGrA rArGrA rUrGrG rUrGrA rCrUrG rCrArG rUrGrG-3'
5'-rArCrU rGrCrA rGrUrC rArCrC rArUrC rUrUrC rUrGrC rCrAG G-3'
HBF Hs.702397_1:
5'-rCrUrU rUrCrA rArGrG rArUrA rGrGrC rUrUrU rArUrU rCrUrG rCrArA-3'
5'-rGrCrA rGrArA rUrArA rArGrC rCrUrA rUrCrC rUrUrG rArAA G-3'
Claims (36)
- in vivoで患者の細胞または組織におけるヘモグロビン(HBF/HBG)ポリヌクレオチドの機能および/または発現を上方制御するための組成物であって、
配列番号3または以下の配列:
GATTTATTAT TTGTATTGCT TGCAGAATAA AGCCTATCCT TGAAAGCTCT 50
GAnTCATGGG CAGTGAGCTC AGTGGnATCT GGnGGnCAGG GCACTGGCCA 100
CTGCAGTCAC CATCTTCTGC CAGGgnGCCT GCACCTCAGG GGTGAnTTCT 150
TTGCCGAAnT GGnTTGCCAA AnCGGTCACC AGCACATTTC CCAGGggCTT 200
GAAGTTCTCA GGnTCCACAT GCAGCTTGTC ACAGTGCAGT TCACTCAGCT 250
GGGCAAAGGT GCCnTTGAGA TCATCCgGGn GCTTTGTGGg nTCTCCCnAG 300
GgnGTCAGnA CCTTCTTGCC ATGTGCCTTG nCTTTGGGGg TTGCCCctgn 350
tgggcag
を有するHBF/HBG遺伝子の天然アンチセンスポリヌクレオチドに特異的にハイブリダイズする、少なくとも1つの長さ15〜30ヌクレオチドのオリゴヌクレオチドを含む、オリゴヌクレオチドアンチセンス化合物を含み、
前記オリゴヌクレオチドが、配列番号4の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号4の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチド、および配列番号14の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号14の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチドである、
組成物。 - 前記オリゴヌクレオチドアンチセンス化合物が、HBF/HBG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。
- 前記オリゴヌクレオチドが、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1に記載の組成物。
- 前記オリゴヌクレオチドが、HBF/HBG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1に記載の組成物。
- 前記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、修飾された核酸塩基および/またはそれらの組合せを含む1または複数の修飾を含む、請求項1に記載の組成物。
- 前記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5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、カルバメート、カーボネート、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5に記載の組成物。
- 前記オリゴヌクレオチドが、ペプチド核酸、またはロックド核酸(LNA)分子を含む少なくとも1つの修飾された核酸塩基を場合により有する、請求項5に記載の組成物。
- in vivoで哺乳動物の細胞または組織におけるHBF/HBG遺伝子の発現および/または機能を増大させるための組成物であって、
配列番号3または以下の配列:
GATTTATTAT TTGTATTGCT TGCAGAATAA AGCCTATCCT TGAAAGCTCT 50
GAnTCATGGG CAGTGAGCTC AGTGGnATCT GGnGGnCAGG GCACTGGCCA 100
CTGCAGTCAC CATCTTCTGC CAGGgnGCCT GCACCTCAGG GGTGAnTTCT 150
TTGCCGAAnT GGnTTGCCAA AnCGGTCACC AGCACATTTC CCAGGggCTT 200
GAAGTTCTCA GGnTCCACAT GCAGCTTGTC ACAGTGCAGT TCACTCAGCT 250
GGGCAAAGGT GCCnTTGAGA TCATCCgGGn GCTTTGTGGg nTCTCCCnAG 300
GgnGTCAGnA CCTTCTTGCC ATGTGCCTTG nCTTTGGGGg TTGCCCctgn 350
tgggcag
を有するHBF/HBG遺伝子の天然アンチセンスポリヌクレオチドに特異的にハイブリダイズする、少なくとも1つの長さ15〜30ヌクレオチドのオリゴヌクレオチドを含む、オリゴヌクレオチドアンチセンス化合物を含み、
前記オリゴヌクレオチドが、配列番号4の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号4の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチド、および配列番号14の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号14の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチドである、
組成物。 - 前記化合物が、HBF/HBGポリヌクレオチドの少なくとも5個の連続する核酸に80%相補的である少なくとも1つのアンチセンスオリゴヌクレオチドを含む、請求項9に記載の組成物。
- 前記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、修飾された核酸塩基および/またはそれらの組合せを含む1または複数の修飾を含む、請求項9に記載の組成物。
- 前記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11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、カルバメート、カーボネート、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11に記載の組成物。
- 前記ヌクレオシド間結合が、少なくとも1つのホスホロチオエート結合を含む、請求項13に記載の組成物。
- 前記修飾された核酸塩基が、ペプチド核酸、ロックド核酸(LNA)分子、またはそれらの組合せを含む、請求項11に記載の組成物。
- 合成修飾オリゴヌクレオチドであって、
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、カルバメート、カーボネート、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む、少なくとも1つの修飾
および
配列番号3または以下の配列:
GATTTATTAT TTGTATTGCT TGCAGAATAA AGCCTATCCT TGAAAGCTCT 50
GAnTCATGGG CAGTGAGCTC AGTGGnATCT GGnGGnCAGG GCACTGGCCA 100
CTGCAGTCAC CATCTTCTGC CAGGgnGCCT GCACCTCAGG GGTGAnTTCT 150
TTGCCGAAnT GGnTTGCCAA AnCGGTCACC AGCACATTTC CCAGGggCTT 200
GAAGTTCTCA GGnTCCACAT GCAGCTTGTC ACAGTGCAGT TCACTCAGCT 250
GGGCAAAGGT GCCnTTGAGA TCATCCgGGn GCTTTGTGGg nTCTCCCnAG 300
GgnGTCAGnA CCTTCTTGCC ATGTGCCTTG nCTTTGGGGg TTGCCCctgn 350
tgggcag
を有するHBF/HBG遺伝子の天然アンチセンスポリヌクレオチドに特異的にハイブリダイズする、少なくとも1つの長さ15〜30ヌクレオチドのオリゴヌクレオチド
を含み、
前記オリゴヌクレオチドが、HBF/HBG分子の発現および/または機能を上方制御するアンチセンス化合物であり、
前記オリゴヌクレオチドが、配列番号4の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号4の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチド、および配列番号14の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号14の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチドである、
合成修飾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、カルバメート、カーボネート、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16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16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16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、および/またはそれらの組合せを含む少なくとも1つの修飾された核酸塩基を場合により含む、請求項16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16に記載のオリゴヌクレオチド。
- HBF/HBGポリヌクレオチドに特異的な1または複数のオリゴヌクレオチドを含む、in vivoで患者の細胞または組織におけるヘモグロビン(HBF/HBG)ポリヌクレオチドの機能および/または発現を上方制御するための組成物であって、
前記オリゴヌクレオチドが、配列番号3または以下の配列:
GATTTATTAT TTGTATTGCT TGCAGAATAA AGCCTATCCT TGAAAGCTCT 50
GAnTCATGGG CAGTGAGCTC AGTGGnATCT GGnGGnCAGG GCACTGGCCA 100
CTGCAGTCAC CATCTTCTGC CAGGgnGCCT GCACCTCAGG GGTGAnTTCT 150
TTGCCGAAnT GGnTTGCCAA AnCGGTCACC AGCACATTTC CCAGGggCTT 200
GAAGTTCTCA GGnTCCACAT GCAGCTTGTC ACAGTGCAGT TCACTCAGCT 250
GGGCAAAGGT GCCnTTGAGA TCATCCgGGn GCTTTGTGGg nTCTCCCnAG 300
GgnGTCAGnA CCTTCTTGCC ATGTGCCTTG nCTTTGGGGg TTGCCCctgn 350
tgggcag
を有するHBF/HBG遺伝子の天然アンチセンスポリヌクレオチドに特異的にハイブリダイズする、少なくとも1つの長さ15〜30ヌクレオチドのオリゴヌクレオチドを含み、
前記オリゴヌクレオチドが、配列番号4の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号4の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチド、および配列番号14の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号14の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチドである、
組成物。 - 前記オリゴヌクレオチドが、配列番号4に記載のヌクレオチド配列と比較して少なくとも90%のヌクレオチド配列同一性を含む、請求項22に記載の組成物。
- 前記オリゴヌクレオチドが、配列番号4に記載のヌクレオチド配列を含む、請求項22に記載の組成物。
- 配列番号4に記載のオリゴヌクレオチド、またはそのアンチセンス配列もしくは相補配列を含む、in vivoで患者の細胞または組織におけるヘモグロビン(HBF/HBG)ポリヌクレオチドの機能および/または発現を上方制御するための組成物。
- 配列番号4に記載のオリゴヌクレオチドが、1または複数の修飾されたまたは置換された核酸塩基を含む、請求項25に記載の組成物。
- 前記修飾された核酸塩基が、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25に記載の組成物。
- 配列番号4に記載のオリゴヌクレオチドが、少なくとも1つのロックド核酸(LNA)分子を含む、請求項25に記載の組成物。
- 前記オリゴヌクレオチドが、配列番号4に記載の配列にアンチセンスまたは相補的な配列を含む、請求項25に記載の組成物。
- in vivoで患者の細胞または組織におけるヘモグロビン(HBF/HBG)ポリヌクレオチドの機能および/または発現を上方制御するための組成物であって、
配列番号3または以下の配列:
GATTTATTAT TTGTATTGCT TGCAGAATAA AGCCTATCCT TGAAAGCTCT 50
GAnTCATGGG CAGTGAGCTC AGTGGnATCT GGnGGnCAGG GCACTGGCCA 100
CTGCAGTCAC CATCTTCTGC CAGGgnGCCT GCACCTCAGG GGTGAnTTCT 150
TTGCCGAAnT GGnTTGCCAA AnCGGTCACC AGCACATTTC CCAGGggCTT 200
GAAGTTCTCA GGnTCCACAT GCAGCTTGTC ACAGTGCAGT TCACTCAGCT 250
GGGCAAAGGT GCCnTTGAGA TCATCCgGGn GCTTTGTGGg nTCTCCCnAG 300
GgnGTCAGnA CCTTCTTGCC ATGTGCCTTG nCTTTGGGGg TTGCCCctgn 350
tgggcag
を有するHBF/HBG遺伝子の天然アンチセンスポリヌクレオチドに特異的にハイブリダイズする、少なくとも1つの長さ15〜30ヌクレオチドのオリゴヌクレオチドを含む、1または複数のアンチセンスまたは相補的オリゴヌクレオチドを含み、
前記オリゴヌクレオチドが、配列番号4の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号4の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチド、および配列番号14の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号14の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチドである、
組成物。 - 1または複数のアンチセンスまたは相補的オリゴヌクレオチドが、HBF/HBGポリヌクレオチド、および/または配列番号1〜2の少なくとも10個の連続する核酸塩基にストリンジェントな条件下でハイブリダイズする、請求項30に記載の組成物。
- 1または複数のアンチセンスまたは相補的オリゴヌクレオチドが、HBF/HBGポリヌクレオチド、および/または配列番号1〜3の少なくとも15個の連続する核酸塩基にストリンジェントな条件下でハイブリダイズする、請求項30に記載の組成物。
- 前記1または複数のアンチセンスまたは相補的オリゴヌクレオチドが、少なくとも15個のヌクレオチドを含む、請求項30に記載の組成物。
- 前記1または複数のアンチセンスまたは相補的オリゴヌクレオチドが、15個から25個のヌクレオチドを含む、請求項30に記載の組成物。
- HBF/HBGポリヌクレオチドに関連する疾患を予防または治療するための組成物であって、
HBF/HBGポリヌクレオチドに結合し、前記HBF/HBGポリヌクレオチドの発現を上方制御する、治療有効量の、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み、
前記アンチセンスオリゴヌクレオチドが、配列番号3または以下の配列:
GATTTATTAT TTGTATTGCT TGCAGAATAA AGCCTATCCT TGAAAGCTCT 50
GAnTCATGGG CAGTGAGCTC AGTGGnATCT GGnGGnCAGG GCACTGGCCA 100
CTGCAGTCAC CATCTTCTGC CAGGgnGCCT GCACCTCAGG GGTGAnTTCT 150
TTGCCGAAnT GGnTTGCCAA AnCGGTCACC AGCACATTTC CCAGGggCTT 200
GAAGTTCTCA GGnTCCACAT GCAGCTTGTC ACAGTGCAGT TCACTCAGCT 250
GGGCAAAGGT GCCnTTGAGA TCATCCgGGn GCTTTGTGGg nTCTCCCnAG 300
GgnGTCAGnA CCTTCTTGCC ATGTGCCTTG nCTTTGGGGg TTGCCCctgn 350
tgggcag
を有するHBF/HBG遺伝子の天然アンチセンスポリヌクレオチドに特異的にハイブリダイズする、少なくとも1つの長さ15〜30ヌクレオチドのオリゴヌクレオチドであり、
前記オリゴヌクレオチドが、配列番号4の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号4の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチド、および配列番号14の塩基配列からなるオリゴヌクレオチドもしくはより短いその断片または前記配列番号14の塩基配列からなるオリゴヌクレオチドもしくは前記より短いその断片を含むオリゴヌクレオチドである、
組成物。 - HBF/HBGポリヌクレオチドに関連する疾患が、関節炎、炎症、神経疾患もしくは障害、自己免疫疾患、癌、細菌性疾患、ウイルス性疾患、または寄生虫を含む、請求項35に記載の組成物。
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