JP2022534086A - 新規の網膜色素変性処置 - Google Patents
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Abstract
Description
本発明は、網膜色素変性の影響を処置、予防、または改善するためのアンチセンスオリゴマーの使用に関する。
網膜色素変性(RP)は、網膜内の桿体光受容細胞の進行性変性によって重度の視力障害を生じる変性眼疾患であり、ほとんどのRPは遺伝性である。この網膜ジストロフィーの形態の初期症状は年齢と無関係に出現し;したがって、RPは、早期乳児期から後期成人期までのあらゆる範囲で診断される。RPは、4000人におよそ1人(全世界で150万人超)が罹患する希少疾患である。家族性RPの症例のうち、30%~40%が常染色体優性遺伝を示す(Hartong et al.2006)。RPの処置方法は現在のところ存在しない。
概して、本発明の1つの態様によれば、CNOT3遺伝子転写物またはその一部においてpre-mRNAスプライシングを改変するための単離または精製されたアンチセンスオリゴマーを提供する。好ましくは、CNOT3遺伝子転写物またはその一部において非産生性スプライシングを誘導するための単離または精製されたアンチセンスオリゴマーを提供する。
a)本明細書中に記載のアンチセンスオリゴマーのうちの1つまたは複数を提供し、前記オリゴマー(1つまたは複数)を標的核酸部位に結合させる工程
を含む、方法も提供する。
a)本明細書中に記載の1つまたは複数のアンチセンスオリゴマーおよび
b)1つまたは複数の薬学的に許容され得る担体および/または希釈剤
を含む、医薬、予防、または治療組成物も提供する。
a)有効量の本明細書中に記載の1つまたは複数のアンチセンスオリゴマーまたは1つまたは複数のアンチセンスオリゴマーを含む医薬組成物を患者に投与する工程
を含む、方法も提供する。
発明の詳細な説明
アンチセンスオリゴヌクレオチド
光受容体は、一般的なスプライシング活性の低下に対する脆弱性が高い。スプライシング因子の変異は種々の組織においてスプライシングの欠陥を引き起こし得るが、光受容細胞は、mRNA産生(ロドプシンおよび他の光伝達タンパク質をコードするmRNAなど)の需要が高いので、大きな影響を受ける。このモデルから、網膜によるmRNAの産生量が他の組織によるmRNAの産生レベルを大きく上回ることが推測される。
a)本明細書中に記載のアンチセンスオリゴマーのうちの1つまたは複数を提供し、前記オリゴマー(1つまたは複数)を標的核酸部位に結合させる工程
を含む、方法も提供する。
1)(i)イントロン-エンハンサー標的モチーフ、(ii)アンチセンスオリゴマーの長さおよびオリゴマーカクテルの開発、(iii)化学の選択、および(iv)オリゴマー送達を向上させるための細胞透過性ペプチド(CPP)の付加の実験での査定による、線維芽細胞の細胞株を使用したin vitroでのオリゴマーの改良;および
2)1つまたは複数のエクソンが喪失したCNOT3転写物を生成するための新規のアプローチの詳細な評価。
本発明のなおさらなる態様によれば、アンチセンスオリゴマーに基づいた治療で用いるための1つまたは複数の本明細書中に記載のアンチセンスオリゴマーを提供する。好ましくは、治療は、CNOT3発現に関する容態のためのものである。より好ましくは、CNOT3発現に関する容態のための治療は、網膜色素変性のための治療である。
a)有効量の本明細書中に記載の1つまたは複数のアンチセンスオリゴマーまたは1つまたは複数のアンチセンスオリゴマーを含む医薬組成物を患者に投与する工程
を含む、方法を提供する。
a)有効量の本明細書中に記載の1つまたは複数のアンチセンスオリゴマーまたは1つまたは複数のアンチセンスオリゴマーを含む医薬組成物を患者に投与する工程
を含む、方法を提供する。
また、本発明のアンチセンスオリゴマーを、疾患の処置のために利用され得る予防薬または治療薬として使用することができる。したがって、1つの実施形態では、本発明は、薬学的に許容され得る担体、希釈剤、または賦形剤と混合された、治療有効量の、CNOT3 pre-mRNA内の選択された標的に結合して本明細書中に記載の効率的かつ一貫したエクソンスキッピングを誘導するアンチセンスオリゴマーを提供する。
a)本明細書中に記載の1つまたは複数のアンチセンスオリゴマー;および
b)1つまたは複数の薬学的に許容され得る担体および/または希釈剤
を含む、医薬、予防、または治療組成物も提供する。
本発明のアンチセンスオリゴマーは、薬学的に許容され得る組成物中で送達させることが好ましい。組成物は、約1nM~1000nMの各々の本発明の所望のアンチセンスオリゴマー(1つまたは複数)を含み得る。好ましくは、組成物は、約1nM~500nM、10nM~500nM、50nM~750nM、10nM~500nM、1nM~100nM、1nM~50nM、1nM~40nM、1nM~30nM、1nM~20nM、最も好ましくは1nMと10nMとの間の本発明の各々の本発明のアンチセンスオリゴマー(1つまたは複数)を含み得る。
本発明の別の態様によれば、CNOT3発現に関連する疾患を調整するか抑制するための医薬の製造における1つまたは複数の本明細書中に記載のアンチセンスオリゴマーの使用を提供する。
患者におけるCNOT3発現に関連する疾患の影響を処置、予防、または改善するためのキットであって、本明細書中に記載の少なくとも1つのアンチセンスオリゴマーおよびその組み合わせまたはカクテルを、使用説明書と共に適切な容器に包装された状態で含む、キットも提供する。
当業者は、本明細書中に記載の発明が具体的に記載した変形形態および修正形態以外の変形形態および修正形態が可能であると認識する。本発明は、全てのかかる変形形態および修正形態を含む。また、本発明は、本明細書中に言及または表示した全ての工程、特徴、製剤、および化合物を個別または集合的に含み、工程または特徴の任意の組み合わせおよび全ての組み合わせまたは任意の2つまたはそれを超える工程または特徴を含む。
H#A/D(x:y)
最初の文字は種を示す(例えば、H:ヒト、M:マウス)
「#」は、標的エクソン番号を示す
「A/D」は、それぞれ、エクソンの最初と最後のアクセプターまたはドナーのスプライス部位を示す
(x y)は、アニーリング座標を表し、ここで、「-」または「+」は、イントロン配列またはエクソン配列をそれぞれ示す。一例として、A(-6+18)は、標的エクソンに先行するイントロンの最後の6塩基および標的エクソンの最初の18塩基を示す。最も近いスプライス部位はアクセプターであると考えられるので、これらの座標は「A」が先行する。ドナースプライス部位でのアニーリング座標の記載はD(+2-18)であり得、ここで、最後の2つのエクソン塩基および最初の18個のイントロン塩基がアンチセンスオリゴマーのアニーリング部位に対応する。全エクソンアニーリング座標は、A(+65+85)(前述のエクソンの最初から65番目のヌクレオチドと85番目のヌクレオチド(両端を含む)の間の部位である)で表される。
CNOT3のフレームシフトを誘導するためのAO媒介エクソンスキッピング
CNOT3のエクソン構造を、図1に示す。スプライススイッチングAOを、CNOT3 pre-mRNA(図1)においてフレームシフトしているエクソン内のエンハンサー部位を標的にして、CNOT3のエクソンスキッピングを誘導し、その結果として、読み取り枠の喪失およびノックダウンを誘導するようにデザインした。
1.エクソン3を標的にするAOのために、エクソン2にアニーリングする順方向プライマーを、エクソン6中の逆方向プライマーとペアにした。
2.エクソン8および9を標的にするAOのために、エクソン7中の順方向プライマーを、エクソン11逆方向プライマーとペアにした。
3.エクソン16および17を標的にするAOのために、エクソン15中の順方向プライマーを、エクソン18中の逆方向プライマーとペアにした。
CNOT3をノックダウンするためのAO媒介末端イントロン保持
アンチセンス配列を、CNOT3の末端エクソンを標的にしてCNOT3の末端イントロン保持およびノックダウンを誘導するようにデザインした。
RPを有する家族の採用および概説
本発明者らは、WA在住のPRPF31変異を有する2家族(コーカサス人の1家族および先住民の1家族)の3世代を試験した(図4)。本発明者らは、患者7人から皮膚線維芽細胞を採取し、これらの家族の24人の罹患個体のうちの10人において疾患進行のモニタリングを開始した。
RP11患者由来の誘導多能性幹細胞および対照線維芽細胞の生成ならびにCNOT3ノックダウンの結果としての遺伝子発現の査定
誘導多能性幹細胞を、患者線維芽細胞および対照線維芽細胞から生成する。患者線維芽細胞を、NEON(登録商標)エレクトロポレーションシステムを使用して、再プログラミングエピソーム(ThermoFisher(登録商標))でトランスフェクトする。典型的な再プログラミング実験では、12~15個のiPSC用コロニーをトランスフェクション3~4週間後に選別し、免疫染色およびRT-PCR分析による多能性遺伝子発現の評価のために継代した(図5A~C)。次いで、3つのクローンを、さらなる試験(TaqMan Arrays(ヒト幹細胞多能性アレイ、ThermoFisher)による遺伝子発現プロファイリングおよびQuantiSNP分析(AGRF)を用いた染色体Gバンド分析によるバーチャル核型分類が含まれる)のために選択する。
AOの用量依存性試験
AO配列を、CNOT3伝令RNA由来の選択されたエクソンをスキッピングするようにデザインし、効率的なトランスフェクションのためのカチオン性リポソームとの複合体化の後に2‘O-メチルホスホロチオアートAOとして線維芽細胞にトランスフェクトした。標的エクソンをスキッピングすると、2%アガロースゲル上の産物の分離および染色によって同定したところ、伝令RNAのRT-PCR産物が短くなる(図6および7)。
アンチセンスオリゴマー媒介CNOT3エクソンスキッピングは、RP11患者のiPSC誘導網膜色素上皮(RPE)におけるPRPF31発現を上方制御し、一次繊毛の長さおよび数をレスキューする
ASO6(配列番号64、CNOT3_H17A(+83+107)、CNOT3エクソン17を標的にする)をホスホロジアミダートモルホリノオリゴマー(PMO)として合成し、培養培地中で5uM ASOを使用した直接トランスフェクションによってRP11 iPSC由来RPEにトランスフェクトした。
チャンバースライド上のRPE細胞を、氷冷アセトン-メタノール(1:1)を用いて4分間固定し、次いで風乾した。細胞を、10%濾過ヤギ血清を含むPBS中で30分間ブロッキングした。基底小体染色のために、細胞を、マウス抗ペリセントリン抗体(1:100)と室温で1時間インキュベートした。一次抗体を、アレキサフルオロ488抗マウス(1:400)を使用して検出した。繊毛染色のために、細胞を、ウサギ抗ARL13B抗体(1:500)とインキュベートし、4℃で一晩インキュベートした。第2の一次抗体を、アレキサフルオロ568抗ウサギ(1:400)を使用して室温で1時間検出し、核検出のためのHoechst(1:125に希釈)を用いて対比染色した。カバーガラスを、Prolong Gold退色防止剤入り培地を使用してスライドガラス上にマウントした。
RPEの一次繊毛を、共焦点顕微鏡法を使用してPRPF31機能を評価するために査定した。およそ300個のRPE細胞/試料の繊毛の長さを、NIS-Elements画像化ソフトウェアを使用して測定した。
Claims (19)
- CNOT3遺伝子転写物またはその一部においてpre-mRNAスプライシングを改変するための単離または精製されたアンチセンスオリゴマー。
- CNOT3遺伝子転写物またはその一部において非産生性スプライシングまたは機能障害を誘導する請求項1に記載のアンチセンスオリゴマー。
- 配列番号1~74を含むリストから選択される請求項1に記載のアンチセンスオリゴマー。
- 前記アンチセンスオリゴマーが、(i)改変されたバックボーン構造;(ii)改変された糖部分;(iii)RNアーゼH耐性;(iv)オリゴマー模倣化学を含むリストから選択される代替の化学または修飾に供された1つまたは複数のヌクレオチドの位置を含む、請求項1に記載のアンチセンスオリゴマー。
- 前記アンチセンスオリゴマーが、(i)部分への化学的コンジュゲート;および/または(ii)細胞透過性ペプチドでのタグ化によってさらに改変されている、請求項1に記載のアンチセンスオリゴマー。
- 前記アンチセンスオリゴマーが、ホスホロジアミダートモルホリノオリゴマーである、請求項1に記載のアンチセンスオリゴマー。
- 任意のウラシル(U)がヌクレオチド配列に存在し、前記ウラシル(U)がチミン(T)に置換されている、請求項1に記載のアンチセンスオリゴマー。
- 前記CNOT3遺伝子転写物またはその一部のエクソンのうちの1つまたは複数のスキッピングを誘導するように作動する請求項1に記載のアンチセンスオリゴマー。
- PRPF31タンパク質の発現が、症候性PRPF31変異を有する被験体におけるPRPF31タンパク質発現の1.5倍と5倍との間になる、請求項1に記載のアンチセンスオリゴマー。
- CNOT3遺伝子転写物のスプライシングを操作する方法であって、
a)請求項1~8のいずれか1項に記載のアンチセンスオリゴマーのうちの1つまたは複数を提供し、前記オリゴマー(1つまたは複数)を標的核酸部位に結合させる工程
を含む、方法。 - 患者におけるCNOT3発現に関する疾患の影響を処置、予防、または改善するための医薬組成物、予防組成物、または治療組成物であって、
a)請求項1~8のいずれか1項に記載の1つまたは複数のアンチセンスオリゴマー、および
b)1つまたは複数の薬学的に許容され得る担体および/または希釈剤
を含む、医薬組成物、予防組成物、または治療組成物。 - CNOT3発現に関連する疾患の影響を処置、予防、または改善する方法であって、
a)有効量の1つまたは複数の請求項1~9のいずれか1項に記載のアンチセンスオリゴマーまたは1つまたは複数のアンチセンスオリゴマーを含む医薬組成物を患者に投与する工程
を含む、方法。 - CNOT3発現に関連する疾患の影響を処置、予防、または改善するための医薬の製造のための請求項1~9のいずれか1項に記載の精製および単離されたアンチセンスオリゴマーの使用。
- 患者におけるCNOT3発現に関連する疾患の影響を処置、予防、または改善するためのキットであって、請求項1~9のいずれか1項に記載の少なくとも1つのアンチセンスオリゴマーおよびその組み合わせまたはカクテルを、使用説明書と共に適切な容器に包装された状態で含む、キット。
- 前記CNOT3発現に関する疾患が網膜色素変性である、請求項11に記載の組成物、請求項10もしくは12に記載の方法、請求項13に記載の使用、または請求項14に記載のキット。
- 前記CNOT3発現に関連する疾患を有する被験体がヒトである、請求項11に記載の組成物、請求項10もしくは12に記載の方法、請求項13に記載の使用、または請求項14に記載のキット。
- 前記PRPF31タンパク質の発現が、症候性PRPF31変異を有する被験体におけるPRPF31タンパク質の発現の1.5と5倍との間になる、請求項11に記載の組成物、請求項10もしくは12に記載の方法、請求項13に記載の使用、または請求項14に記載のキット。
- 配列番号4、7、9、11、15、16~18、27、30、34、35、および64を含むリストから選択される、請求項1に記載のアンチセンスオリゴマー。
- 配列番号4、7、27、30、34、および64を含むリストから選択される、請求項1に記載のアンチセンスオリゴマー。
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2020
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- 2020-05-25 AU AU2020285470A patent/AU2020285470A1/en active Pending
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- 2020-05-25 CA CA3141633A patent/CA3141633A1/en active Pending
- 2020-05-25 CN CN202080040006.5A patent/CN113891940A/zh active Pending
- 2020-05-25 EP EP20813543.4A patent/EP3976789A4/en active Pending
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SG11202112946VA (en) | 2021-12-30 |
EP3976789A1 (en) | 2022-04-06 |
WO2020237294A1 (en) | 2020-12-03 |
CN113891940A (zh) | 2022-01-04 |
CA3141633A1 (en) | 2020-12-03 |
EP3976789A4 (en) | 2023-08-09 |
KR20220012276A (ko) | 2022-02-03 |
BR112021023936A2 (pt) | 2022-01-25 |
AU2020285470A1 (en) | 2021-12-16 |
US20220298506A1 (en) | 2022-09-22 |
IL288442A (en) | 2022-01-01 |
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