JP2021531829A - 環状化された遺伝子操作rna及び方法 - Google Patents
環状化された遺伝子操作rna及び方法 Download PDFInfo
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Abstract
Description
本出願は、全体として参照により本明細書中に取り込まれる、2018年7月24日出願の米国特許仮出願第62/702,853号の利益を主張するものである。
RIBOMAX T7インビトロ転写キット(Promega、ウィスコンシン州マディソン)を用い、以下の表1に明記された反応条件が用いられた。対照テンプレートが、約1800塩基の直鎖状生成物を作り出すためにキット内に提供されている。
ceRNA構築物が、pET 24a(+)プラスミドにクローニングされ、BL21 Star(DE3)大腸菌中に形質転換された。培養物は、OD600で吸光度0.7になるまで30℃で生育された。RNA転写が、5mM IPTGで30分間誘導され、その時点で100μg/mLのクロラムフェニコールが図4の8と表記されたレーンに添加された。クロラムフェニコールが添加された20分後、合計50分間の誘導の後に、バクテリア培養物が回収された。RNeasy miniキット(Qiagen、ドイツ ヒルデン)が用いられて、3回の凍結解凍サイクルの添加でRNAを抽出し、細胞壁及び膜の破壊を補助した。反応物が、以下の表4に示される通り調製された。
HEK293T細胞が、トランスフェクションの前夜に50,000細胞/ウェルで24ウェルプレートに播種された。ceRNAをコードするDNAプラスミド又は直接ceRNAのどちらかが、以下の表5に明記される通り、LIPOFECTAMINE STEM試薬(Thermo Fisher Scientific、マサチューセッツ州ウォルサム)を用いて、製造業者の指導に従ってトランスフェクトされた。
真核細胞が、前夜に100,000細胞/ウェルで播種され、以下の表6に明記される通り、LIPOFECTAMINE STEM試薬(Thermo Fisher Scientific、マサチューセッツ州ウォルサム)を用いて、ceRNAをコードするDNAでトランスフェクトされた。
配列番号1 − 例示的な細胞外小胞標的配列
GGGACGACGATGACACGATACTTTGTCGGCCGAACTCGCTGCTCCGATCCGGCGAGATCGCAGGGTGTTGCTATTCGCGTGCCGTGTGCATACGCCGATCACATGACCAGGGACGACGATGACACGATACTTTGTCGGCCGAACTCGCTGTTTAACTGCCCGGCGAGATCGCAGGGTGTTGTGCTATTCGCGTGCCGTGTGCATACGCCGATCACATGACCAACCCTGCCGCCTGGACTCCGCCTGT
ACCGACCAGAATCATGCAAGTGCGTAAGATAGTCGCGGGCCGGG
ACCAGGCUUGGA
UCACAUGG
CUUGGAAGCAGA
UCUUCUCGGAUU
GGCCAGGGGUUC
AGGAACGAAC
UAUGUGGCCAUC
ACCAGGCUUGGA
CAGCGAGACC
CUCACUUGGGAG
AGCACCACCU
CAGGAGUCUACA
GGAGAAGAAGGC
GGGGAACCUGCA
ACCAAUGGGG
GGGGAACCUGCA
Claims (35)
- ポリヌクレオチドであって、以下:
転写単位であって、
前記転写単位の5’末端にある第一の配列、及び前記転写単位の3’末端にある第二の配列を含む環状化エレメントと、
前記環状化エレメントの第一の配列と、前記環状化エレメントの前記第二の配列との間にある少なくとも1つのコード領域と、
前記コード領域に動作可能に連結された内部リボソーム進入部位(internal ribosome entry site)(IRES)と、
を含む、転写単位;並びに
前記転写単位に動作可能に連結されたプロモータ、
を含む、ポリヌクレオチド。 - DNAを含む、請求項1に記載のポリヌクレオチド。
- RNAを含む、請求項1に記載のポリヌクレオチド。
- 前記環状化エレメントの前記第一の配列が、バクテリオファージRNAのチミジル酸シンセターゼ(td)からのイントロンの第一の部分を含み;かつ
前記環状化エレメントの前記第二の配列が、バクテリオファージRNAのチミジル酸シンセターゼ(td)からの前記イントロンの第二の部分を含む、
請求項1に記載のポリヌクレオチド。 - 前記環状化エレメントの前記第一の配列が、真核生物スプライス受容配列を含み;かつ
前記環状化エレメントの前記第二の配列が、真核生物スプライス供与配列を含む、
請求項1に記載のポリヌクレオチド。 - 前記IRESが、クリケット麻痺ウイルスIRES(CrPV−IRES)又はチャバネアオカメムシ腸管ウイルスIRES(Plautia stali intestine virus IRES)(PSIV−IRES)を含む、請求項1〜5のいずれかに記載のポリヌクレオチド。
- 前記コード領域が、治療用ペプチドをコードする、請求項1〜6のいずれかに記載のポリヌクレオチド。
- 前記IRESが、少なくとも2つのコード領域に動作可能に連結されている、請求項1〜7のいずれかに記載のポリヌクレオチド。
- 第二のコード領域に動作可能に連結された第二のIRESをさらに含む、請求項1〜8のいずれかに記載のポリヌクレオチド。
- 前記転写単位が、以下:
三重らせんモチーフ;
非翻訳領域(UTR);
RNA安定性エレメント;
RNA輸送エレメント若しくはRNA局在化エレメント;又は
アフィニティ精製アプタマー、
をさらに含む、請求項1〜9のいずれかに記載のポリヌクレオチド。 - 前記UTRが、miRNA結合部位又は細胞外小胞標的配列を含む、請求項10に記載のポリヌクレオチド。
- 前記RNA安定性エレメントが、ウッドチャック肝炎転写後調節エレメント(WPRE)を含む、請求項10に記載のポリヌクレオチド。
- 前記RNA輸送エレメントが、細胞核からのRNAの輸送を促進する配列を含む、請求項10に記載のポリヌクレオチド。
- 環状RNA分子であって、以下:
少なくとも1つのコード領域と;
前記コード領域に動作可能に連結された内部リボソーム進入部位(IRES)と、
を含む、環状RNA分子。 - 前記IRESが、クリケット麻痺ウイルスIRES(CrPV−IRES)又はチャバネアオカメムシ腸管ウイルスIRES(PSIV−IRES)を含む、請求項14に記載の環状RNA分子。
- 前記コード領域が、治療用ペプチドをコードする、請求項14又は15に記載の環状RNA分子。
- 前記IRESが、少なくとも2つのコード領域に動作可能に連結されている、請求項14〜16のいずれか1項に記載の環状RNA分子。
- 第二のコード領域に動作可能に連結された第二のIRESをさらに含む、請求項14〜17のいずれか1項に記載の環状RNA分子。
- 三重らせんモチーフ;
非翻訳領域(UTR);
RNA安定性エレメント;
RNA輸送エレメント若しくはRNA局在化エレメント;又は
アフィニティ精製アプタマー、
をさらに含む、請求項14に記載の環状RNA分子。 - 前記UTRが、miRNA結合部位又は細胞外小胞標的配列を含む、請求項19に記載の環状RNA分子。
- 前記RNA安定性エレメントが、ウッドチャック肝炎転写後調節エレメント(WPRE)、大腸菌(E. coli)REPエレメント、又はベータ−グロビン安定性エレメントを含む、請求項19に記載の環状RNA分子。
- 前記RNA輸送エレメントが、細胞核からのRNAの輸送を促進する配列を含む、請求項19に記載の環状RNA分子。
- 請求項1〜13のいずれか1項に記載のポリヌクレオチドで形質転換された細胞。
- 請求項14〜22のいずれか1項に記載の環状RNAを含む細胞。
- 前記環状RNAが、前記細胞の外部で合成される、請求項24に記載の細胞。
- 前記環状RNAが、前記細胞により合成される、請求項24に記載の細胞。
- エクソソームをさらに含む、請求項26に記載の細胞。
- 前記細胞内の前記環状RNA分子の少なくとも一部が、前記エクソソーム内に置かれている、請求項27に記載の細胞。
- 環状RNA分子を作製する方法であって、以下:
請求項1〜13のいずれか1項に記載のポリヌクレオチドで宿主細胞を形質転換すること;
前記宿主細胞に前記ポリヌクレオチドからの直鎖状RNA分子を転写させること;及び
前記環状化エレメントに前記直鎖状RNA分子を環状化させ、それにより環状RNA分子を形成させること、
を含む、方法。 - 前記環状RNA分子の少なくとも一部を前記宿主細胞から単離することをさらに含む、請求項29に記載の方法。
- 直鎖状RNA分子をRNaseで消化すること;及び
未消化の環状RNA分子を回収すること、
をさらに含む、請求項30に記載の方法。 - 前記環状RNA分子が、前記環状RNAを前記宿主細胞内のエクソソームに移動させるのに効果的な細胞外小胞標的配列を含む、請求項29に記載の方法。
- 前記環状RNA分子を含有するエクソソームを単離することをさらに含む、請求項32に記載の方法。
- 治療用ペプチドにより提供される治療を必要とする対象を処置する方法であって、
前記コード領域が前記治療用ペプチドをコードする、請求項1〜13のいずれか1項に記載のポリヌクレオチド;又は
前記コード領域が前記治療用ペプチドをコードする、請求項14〜22のいずれか1項に記載の環状RNA分子、
を前記対象に投与することを含む、方法。 - 前記環状RNAを前記対象に投与することが、環状化されたRNAを含有するエクソソームを前記対象に投与することを含む、請求項34に記載の方法。
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EP3826643A4 (en) | 2022-05-18 |
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WO2020023595A9 (en) | 2020-03-26 |
US20210277393A1 (en) | 2021-09-09 |
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