JP2023503202A - アンチセンスオリゴヌクレオチドおよびペンドレッド症候群を処置するためのそれらの使用 - Google Patents
アンチセンスオリゴヌクレオチドおよびペンドレッド症候群を処置するためのそれらの使用 Download PDFInfo
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Abstract
Description
本出願は、2020年2月12日に出願された米国仮特許出願第62/975,337号の優先権を主張し、その全ての内容が援用により本明細書に取り込まれる。
本出願は、ASCII様式にて電子的に提出された配列表を含み、この配列表の全体が援用により本明細書に組み込まれる。2021年2月10日に作成されたこのASCIIのコピーは、ファイル名が「13365_0018-00304_SL.txt」であり、サイズが16,709バイトである。
本発明は、mRNA前駆体スプライシング中にエクソンスキッピングを防止または低減するための新規なアンチセンスオリゴヌクレオチド(「ASO」)、当該ASOを含有する医薬組成物、およびそれらの使用に関する。
a.HUA0003-1027(5’-tagtactaagaggaacac-3’)(配列番号:2)、
b.HUA0003-1029(5’-attagtactaagaggaacac-3’)(配列番号:3)、
c.HUA0003-1030(5’-tattagtactaagaggaacac-3’)(配列番号:4)、
d.HUA0003-1031(5’-gtattagtactaagaggaacac-3’)(配列番号:5)、
e.HUA0003-1032(5’-tgtattagtactaagaggaacac-3’)(配列番号:6)、
f.HUA0003-0930(5’-tattagtactaagaggaacacc-3’)(配列番号:7)、
g.HUA0003-0929(5’-attagtactaagaggaacacc-3’)(配列番号:8)、
h.HUA0003-0928(5’-ttagtactaagaggaacacc-3’)(配列番号:9)、または
i.HUA0003-0931(5’-gtattagtactaagaggaacacc-3’)(配列番号:10)である。
a.HUA0003-1027(5’-tagtactaagaggaacac-3’)(配列番号:2)、
b.HUA0003-1029(5’-attagtactaagaggaacac-3’)(配列番号:3)、
c.HUA0003-1030(5’-tattagtactaagaggaacac-3’)(配列番号:4)、
d.HUA0003-1031(5’-gtattagtactaagaggaacac-3’)(配列番号:5)、
e.HUA0003-1032(5’-tgtattagtactaagaggaacac-3’)(配列番号:6)、
f.HUA0003-0930(5’-tattagtactaagaggaacacc-3’)(配列番号:7)、
g.HUA0003-0929(5’-attagtactaagaggaacacc-3’)(配列番号:8)、
h.HUA0003-0928(5’-ttagtactaagaggaacacc-3’)(配列番号:9)、または
i.HUA0003-0931(5’-gtattagtactaagaggaacacc-3’)(配列番号:10)である。
a.HUA0003-1027(5’-tagtactaagaggaacac-3’)(配列番号:2)、
b.HUA0003-1029(5’-attagtactaagaggaacac-3’)(配列番号:3)、
c.HUA0003-1030(5’-tattagtactaagaggaacac-3’)(配列番号:4)、
d.HUA0003-1031(5’-gtattagtactaagaggaacac-3’)(配列番号:5)、
e.HUA0003-1032(5’-tgtattagtactaagaggaacac-3’)(配列番号:6)、
f.HUA0003-0930(5’-tattagtactaagaggaacacc-3’)(配列番号:7)、
g.HUA0003-0929(5’-attagtactaagaggaacacc-3’)(配列番号:8)、
h.HUA0003-0928(5’-ttagtactaagaggaacacc-3’)(配列番号:9)、または
i.HUA0003-0931(5’-gtattagtactaagaggaacacc-3’)(配列番号:10)である。
a.HUA0003-1027(5’-tagtactaagaggaacac-3’)(配列番号:2)、
b.HUA0003-1029(5’-attagtactaagaggaacac-3’)(配列番号:3)、
c.HUA0003-1030(5’-tattagtactaagaggaacac-3’)(配列番号:4)、
d.HUA0003-1031(5’-gtattagtactaagaggaacac-3’)(配列番号:5)、
e.HUA0003-1032(5’-tgtattagtactaagaggaacac-3’)(配列番号:6)、
f.HUA0003-0930(5’-tattagtactaagaggaacacc-3’)(配列番号:7)、
g.HUA0003-0929(5’-attagtactaagaggaacacc-3’)(配列番号:8)、
h.HUA0003-0928(5’-ttagtactaagaggaacacc-3’)(配列番号:9)、または
i.HUA0003-0931(5’-gtattagtactaagaggaacacc-3’)(配列番号:10)である。
a.HUA0003-1027(5’-tagtactaagaggaacac-3’)(配列番号:2)、
b.HUA0003-1029(5’-attagtactaagaggaacac-3’)(配列番号:3)、
c.HUA0003-1030(5’-tattagtactaagaggaacac-3’)(配列番号:4)、
d.HUA0003-1031(5’-gtattagtactaagaggaacac-3’)(配列番号:5)、
e.HUA0003-1032(5’-tgtattagtactaagaggaacac-3’)(配列番号:6)、
f.HUA0003-0930(5’-tattagtactaagaggaacacc-3’)(配列番号:7)、
g.HUA0003-0929(5’-attagtactaagaggaacacc-3’)(配列番号:8)、
h.HUA0003-0928(5’-ttagtactaagaggaacacc-3’)(配列番号:9)、または
i.HUA0003-0931(5’-gtattagtactaagaggaacacc-3’)(配列番号:10)である。
本明細書で使用される用語「オリゴヌクレオチド」は、少なくとも10個のDNAまたはRNAヌクレオチドを含むヌクレオチド配列を指す。
一実施形態では、本明細書は、SLC26A4mRNA前駆体中の標的配列に向けられるASOを開示する。いくつかの実施形態は、SLC26A4mRNA前駆体中のイントロン8の25ヌクレオチド標的配列(表1、「対象25-Nt配列」)の全部または一部に向けられるASOに関する。この標的配列は、SLC26A4遺伝子中のイントロン8の8位から32位までの配列である。このイントロン8標的配列は、変異体(c.919-2A>G)SLC26A4で発生するエクソン8スキッピングに含まれることで、変異体を含むmRNA前駆体が不正確にスプライシングされ、最終転写産物からエクソン8が除去される。
別の実施形態では、開示されるASOは、当業者に知られている1つまたは複数の方法で化学的に修飾された1つまたは複数のヌクレオチドを含む。ヌクレオチド修飾は、例えば、修飾窒素塩基、糖部分、およびリン酸塩を含む。このような修飾は、少なくともヌクレアーゼ分解に耐性がある点において好ましい。
本発明に従って使用されるアンチセンス分子は、固相合成の周知の技術によって作製され得る。このような合成のための設備は、例えば、Applied Biosystems(Foster City, Calif.)を含めたいくつかの供給業者によって販売されている。修飾された固体支持体上でオリゴヌクレオチドを合成するための1つの方法は、米国特許第4,458,066号に記載されている。
上述したASOは、変異体(c.919-2A>G)SLC26A4遺伝子から転写されたmRNA前駆体の処理中にエクソン8スキッピングを防止または低減するために使用可能である。
上述したASOは、ペンドレッド症候群を有する対象における難聴を処置するために使用可能である。
ASOと薬学的に許容される担体または賦形剤とを含む医薬組成物は、製薬業界でよく知られている技術によって投与のために調製することができる。このような技術は、ASOを担体および/または賦形剤と組み合わせて単位投与形態で会合させることを含むが、これに限定されない。
2’-O-メトキシエチル(MOE)リボース、ホスホロチオエート(PS)骨格で修飾され、すべてのシトシンの代わりに5-メチルシトシンを含むASOを、Biosyntech(Suzhou, China)から購入して、20uMのストック溶液でDEPC処理水に溶解した。153-ntエクソン7、100-ntイントロン7、83-ntエクソン8、短縮701-ntイントロン8(382+6+313)、148-ntエクソン9、およびイントロン9の最初の27-nt配列を含むヒトSLC26A4ミニ遺伝子c.919-2A>G変異体(1211bp)を2段階のプロセスを経てpCI-neoベクターで構築した。まず、718-ntのゲノムDNA断片(エクソン7からイントロン8の最初の382-bp配列まで)をベクター内の制限部位XholとXbalでクローニングし、次に488-bpのゲノムDNA断片(イントロン8の最後の313-bp配列からイントロン9の最初の27-nt配列まで)を制限部位XbalとNotIでクローニングした。
2A>G変異を有するヒトSLC26A4エクソン8
エクソン8(大文字)、隣接するイントロン配列(小文字)およびc.919-2A>G変異(g)は、以下のとおりである。
Claims (28)
- 配列番号:1(5’-tgtattagtactaagaggaacacca-3’)の全部または一部を含む、10~30ヌクレオチドの長さを有するアンチセンスオリゴヌクレオチド。
- 前記アンチセンスオリゴヌクレオチドは、
a.HUA0003-1027(5’-tagtactaagaggaacac-3’)(配列番号:2)、
b.HUA0003-1029(5’-attagtactaagaggaacac-3’)(配列番号:3)、
c.HUA0003-1030(5’-tattagtactaagaggaacac-3’)(配列番号:4)、
d.HUA0003-1031(5’-gtattagtactaagaggaacac-3’)(配列番号:5)、
e.HUA0003-1032(5’-tgtattagtactaagaggaacac-3’)(配列番号:6)、
f.HUA0003-0930(5’-tattagtactaagaggaacacc-3’)(配列番号:7)、
g.HUA0003-0929(5’-attagtactaagaggaacacc-3’)(配列番号:8)、
h.HUA0003-0928(5’-ttagtactaagaggaacacc-3’)(配列番号:9)、または
i.HUA0003-0931(5’-gtattagtactaagaggaacacc-3’)(配列番号:10)である、請求項1に記載のアンチセンスオリゴヌクレオチド。 - 前記アンチセンスオリゴヌクレオチドは非天然骨格を含む、請求項1に記載のアンチセンスオリゴヌクレオチド。
- 前記非天然骨格は修飾糖部分を含む、請求項3に記載のアンチセンスオリゴヌクレオチド。
- 前記修飾糖部分は2’-O-メトキシエチルリボースを含む、請求項4に記載のアンチセンスオリゴヌクレオチド。
- 前記非天然骨格は修飾リン酸塩を含む、請求項3に記載のアンチセンスオリゴヌクレオチド。
- 前記修飾リン酸塩は、ホスホロチオエートを含む、請求項6に記載のアンチセンスオリゴヌクレオチド。
- 前記アンチセンスオリゴヌクレオチドは修飾窒素塩基を含む、請求項1に記載のアンチセンスオリゴヌクレオチド。
- 前記修飾窒素塩基は5-メチルシトシン塩基を含む、請求項8に記載のアンチセンスオリゴヌクレオチド。
- 薬学的に許容される担体または賦形剤をさらに含む、請求項1に記載のアンチセンスオリゴヌクレオチド。
- mRNA前駆体スプライシング中にSLC26A4遺伝子におけるエクソン8スキッピングを防止または低減する方法であって、核酸分子を細胞に導入することを含み、前記核酸分子は、配列番号:1(5’-tgtattagtactaagaggaacacca-3’)の全部または一部を含むアンチセンスオリゴヌクレオチドであり、前記オリゴヌクレオチドは、SLC26A4遺伝子のイントロン8標的領域にハイブリダイズし、SLC26A4遺伝子のmRNA前駆体スプライシング中にエクソン8スキッピングを防止または低減する、方法。
- 前記アンチセンスオリゴヌクレオチドは、
a.HUA0003-1027(5’-tagtactaagaggaacac-3’)(配列番号:2)、
b.HUA0003-1029(5’-attagtactaagaggaacac-3’)(配列番号:3)、
c.HUA0003-1030(5’-tattagtactaagaggaacac-3’)(配列番号:4)、
d.HUA0003-1031(5’-gtattagtactaagaggaacac-3’)(配列番号:5)、
e.HUA0003-1032(5’-tgtattagtactaagaggaacac-3’)(配列番号:6)、
f.HUA0003-0930(5’-tattagtactaagaggaacacc-3’)(配列番号:7)、
g.HUA0003-0929(5’-attagtactaagaggaacacc-3’)(配列番号:8)、
h.HUA0003-0928(5’-ttagtactaagaggaacacc-3’)(配列番号:9)、または
i.HUA0003-0931(5’-gtattagtactaagaggaacacc-3’)(配列番号:10)である、請求項11に記載の方法。 - 前記細胞は動物細胞である、請求項11に記載の方法。
- 前記細胞はヒト細胞である、請求項13に記載の方法。
- 前記核酸分子は、発現ベクターによって細胞内に導入される、請求項11に記載の方法。
- 前記発現ベクターはpCI-neo発現ベクターである、請求項15に記載の方法。
- 治療上有効量の請求項1に記載のアンチセンスオリゴヌクレオチドを投与することを含む、ペンドレッド症候群を有する対象における難聴を処置する方法。
- 前記アンチセンスオリゴヌクレオチドは、
a.HUA0003-1027(5’-tagtactaagaggaacac-3’)(配列番号:2)、
b.HUA0003-1029(5’-attagtactaagaggaacac-3’)(配列番号:3)、
c.HUA0003-1030(5’-tattagtactaagaggaacac-3’)(配列番号:4)、
d.HUA0003-1031(5’-gtattagtactaagaggaacac-3’)(配列番号:5)、
e.HUA0003-1032(5’-tgtattagtactaagaggaacac-3’)(配列番号:6)、
f.HUA0003-0930(5’-tattagtactaagaggaacacc-3’)(配列番号:7)、
g.HUA0003-0929(5’-attagtactaagaggaacacc-3’)(配列番号:8)、
h.HUA0003-0928(5’-ttagtactaagaggaacacc-3’)(配列番号:9)、または
i.HUA0003-0931(5’-gtattagtactaagaggaacacc-3’)(配列番号:10)である、請求項17に記載の方法。 - 前記アンチセンスオリゴヌクレオチドは非経口投与により投与される、請求項17に記載の方法。
- mRNA前駆体スプライシング中にSLC26A4遺伝子におけるエクソン8スキッピングを防止または低減する方法に用いる請求項1に記載の化合物であって、核酸分子を細胞内に導入することを含み、前記核酸分子は、配列番号:1(5’-tgtattagtactaagaggaacacca-3’)の全部または一部を含むアンチセンスオリゴヌクレオチドであり、前記オリゴヌクレオチドは、SLC26A4遺伝子のイントロン8標的領域にハイブリダイズし、SLC26A4遺伝子のmRNA前駆体スプライシング中にエクソン8スキッピングを防止または低減する、化合物。
- 前記アンチセンスオリゴヌクレオチドは、
a.HUA0003-1027(5’-tagtactaagaggaacac-3’)(配列番号:2)、
b.HUA0003-1029(5’-attagtactaagaggaacac-3’)(配列番号:3)、
c.HUA0003-1030(5’-tattagtactaagaggaacac-3’)(配列番号:4)、
d.HUA0003-1031(5’-gtattagtactaagaggaacac-3’)(配列番号:5)、
e.HUA0003-1032(5’-tgtattagtactaagaggaacac-3’)(配列番号:6)、
f.HUA0003-0930(5’-tattagtactaagaggaacacc-3’)(配列番号:7)、
g.HUA0003-0929(5’-attagtactaagaggaacacc-3’)(配列番号:8)、
h.HUA0003-0928(5’-ttagtactaagaggaacacc-3’)(配列番号:9)、または
i.HUA0003-0931(5’-gtattagtactaagaggaacacc-3’)(配列番号:10)である、請求項20に記載の化合物。 - 前記細胞は動物細胞である、請求項20に記載の化合物。
- 前記細胞はヒト細胞である、請求項22に記載の化合物。
- 前記核酸分子は発現ベクターを介して細胞内に導入される、請求項20に記載の化合物。
- 前記発現ベクターはpCI-neo発現ベクターである、請求項24に記載の化合物。
- ペンドレッド症候群を有する対象における難聴を処置する方法に用いる請求項1に記載の化合物であって、治療上有効量の請求項1に記載のアンチセンスオリゴヌクレオチドを投与することを含む、化合物。
- 前記アンチセンスオリゴヌクレオチドは、
a.HUA0003-1027(5’-tagtactaagaggaacac-3’)(配列番号:2)、
b.HUA0003-1029(5’-attagtactaagaggaacac-3’)(配列番号:3)、
c.HUA0003-1030(5’-tattagtactaagaggaacac-3’)(配列番号:4)、
d.HUA0003-1031(5’-gtattagtactaagaggaacac-3’)(配列番号:5)、
e.HUA0003-1032(5’-tgtattagtactaagaggaacac-3’)(配列番号:6)、
f.HUA0003-0930(5’-tattagtactaagaggaacacc-3’)(配列番号:7)、
g.HUA0003-0929(5’-attagtactaagaggaacacc-3’)(配列番号:8)、
h.HUA0003-0928(5’-ttagtactaagaggaacacc-3’)(配列番号:9)、または
i.HUA0003-0931(5’-gtattagtactaagaggaacacc-3’)(配列番号:10)である、請求項26に記載の化合物。 - 前記アンチセンスオリゴヌクレオチドは非経口投与により投与される、請求項26に記載の化合物。
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