JP2020186266A - mRNA送達のための脂質ナノ粒子組成物および方法 - Google Patents
mRNA送達のための脂質ナノ粒子組成物および方法 Download PDFInfo
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- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/644—Coagulation factor IXa (3.4.21.22)
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
- C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
- C12Y302/01022—Alpha-galactosidase (3.2.1.22)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21022—Coagulation factor IXa (3.4.21.22)
Abstract
Description
これまでに、mRNAコード抗原での免疫化等の低レベルの翻訳が制限要素ではなかった適用においてのみ、mRNA遺伝子治療を用いて著しい進歩がもたらされている。ネイキッドまたはプロタミン複合体mRNAの皮内注入による腫瘍抗原に対するワクチン接種を含む臨床試験は、実行可能性、毒性欠如、および有望な結果を実証した。X.Su et al.,Mol.Pharmaceutics 8:774−787(2011)。残念ながら、低レベルの翻訳は、生物学的影響または治療的影響を与えるためにより高いレベルのmRNAコードタンパク質の持続発現を必要とする他の適用におけるmRNAベースの遺伝子治療の活用を大いに制限している。
(項目1)
(a)少なくとも一部が機能的分泌性ポリペプチドをコードする少なくとも1つのmRNA分子と、(b)脂質ナノ粒子を含む移送ビヒクルと、を含む、組成物。
(項目2)
前記mRNAは、リソソーム貯蔵障害を有する個体において異常に欠乏している酵素をコードする、項目1に記載の組成物。
(項目3)
前記mRNAは、機能的エリスロポエチンまたは機能的α−ガラクトシダーゼポリペプチドをコードする、項目1に記載の組成物。
(項目4)
前記RNA分子は、前記RNA分子に安定性を付与する少なくとも1つの修飾を含む、項目1に記載の組成物。
(項目5)
前記RNA分子は、前記RNA分子の5’非翻訳領域の修飾を含む、項目1に記載の組成物。
(項目6)
前記修飾は、Cap1構造の包含を含む、項目5に記載の組成物。
(項目7)
前記RNA分子は、前記RNA分子の3’非翻訳領域の修飾を含む、項目1に記載の組成物。
(項目8)
前記修飾は、ポリA尾部の包含を含む、項目7に記載の組成物。
(項目9)
標的細胞の細胞内コンパートメントへの前記RNA分子の移動を促進するための作用物質をさらに含む、項目1に記載の組成物。
(項目10)
前記脂質ナノ粒子は、1つ以上のカチオン性脂質を含む、項目1に記載の組成物。
(項目11)
前記脂質ナノ粒子は、1つ以上の非カチオン性脂質を含む、項目1に記載の組成物。
(項目12)
前記脂質ナノ粒子は、1つ以上のPEG修飾脂質を含む、項目1に記載の組成物。
(項目13)
前記脂質ナノ粒子は、C12−200を含む、項目1に記載の組成物。
(項目14)
前記脂質ナノ粒子は、DLinKC2DMA、CHOL、DOPE、およびDMG−PEG−2000を含む、項目1に記載の組成物。
(項目15)
前記脂質ナノ粒子は、C12−200、DOPE、CHOL、およびDMGPEG2Kを含む、項目1に記載の組成物。
(項目16)
前記脂質ナノ粒子は、切断可能な脂質を含む、項目1に記載の組成物。
(項目17)
前記組成物は、凍結乾燥される、項目1に記載の組成物。
(項目18)
前記組成物は、凍結乾燥された再構成組成物である、項目1に記載の組成物。
(項目19)
前記標的細胞は、肝細胞、上皮細胞、造血細胞、上皮細胞、内皮細胞、肺細胞、骨細胞、幹細胞、間葉細胞、神経細胞、心臓細胞、含脂肪細胞、血管平滑筋細胞、心筋細胞、骨格筋細胞、β細胞、下垂体細胞、滑膜ライニング細胞、卵巣細胞、精巣細胞、線維芽細胞、B細胞、T細胞、網状赤血球、白血球、顆粒球、および腫瘍細胞からなる群から選択される、項目10に記載の組成物。
(項目20)
機能的ポリペプチドが欠乏している対象を治療する方法であって、(a)少なくとも一部が前記機能的分泌性ポリペプチドをコードする少なくとも1つのmRNAと、(b)脂質ナノ粒子を含む移送ビヒクルと、を含む組成物を投与することを含み、前記組成物の投与後、前記mRNAは、標的細胞内で発現されて、前記機能的分泌性ポリペプチドを産生する、方法。
(項目21)
前記mRNAは、機能的エリスロポエチン、α−ガラクトシダーゼ、LDL受容体、第VIII因子、第IX因子、α−L−イズロニダーゼ、イズロン酸スルファターゼ、ヘパリン−N−スルファターゼ、α−N−アセチルグルコサミニダーゼ、ガラクトース6−スルファターゼ、β−ガラクトシダーゼ、リソソーム酸リパーゼまたはアリールスルファターゼ−Aポリペプチド、および(b)移送ビヒクルをコードし、前記組成物の投与後、前記mRNAは、標的細胞内で発現されて、機能的分泌性ポリペプチドを産生する、項目21に記載の方法。
(項目22)
前記機能的分泌性ポリペプチドは、リソソーム貯蔵障害を有する個体において異常に欠乏している酵素である、項目21に記載の方法。
(項目23)
前記mRNA分子は、前記mRNA分子に安定性を付与する少なくとも1つの修飾を含む、項目21に記載の方法。
(項目24)
前記mRNA分子は、前記mRNA分子の5’非翻訳領域の修飾を含む、項目21に記載の方法。
(項目25)
前記修飾は、Cap1構造の包含を含む、項目25に記載の方法。
(項目26)
前記mRNA分子は、前記mRNA分子の3’非翻訳領域の修飾を含む、項目21に記載の方法。
(項目27)
前記修飾は、ポリA尾部の包含を含む、項目27に記載の方法。
(項目28)
前記標的細胞の細胞内コンパートメントへの前記mRNA分子の移動を促進するための作用物質をさらに含む、項目21に記載の方法。
(項目29)
前記脂質ナノ粒子は、1つ以上のカチオン性脂質を含む、項目21に記載の方法。
(項目30)
前記脂質ナノ粒子は、1つ以上の非カチオン性脂質を含む、項目21に記載の方法。
(項目31)
前記脂質ナノ粒子は、1つ以上のPEG修飾脂質を含む、項目21に記載の方法。
(項目32)
前記脂質ナノ粒子は、C12−200を含む、項目21に記載の方法。
(項目33)
前記脂質ナノ粒子は、DLinKC2DMA、CHOL、DOPE、およびDMG−PEG−2000を含む、項目21に記載の方法。
(項目34)
前記脂質ナノ粒子は、C12−200、DOPE、CHOL、およびDMGPEG2Kを含む、項目21に記載の方法。
(項目35)
前記脂質ナノ粒子は、切断可能な脂質を含む、項目21に記載の方法。
(項目36)
前記組成物は、凍結乾燥される、項目21に記載の方法。
(項目37)
前記組成物は、凍結乾燥された再構成組成物である、項目21に記載の方法。
(項目38)
前記標的細胞は、肝細胞、上皮細胞、造血細胞、上皮細胞、内皮細胞、肺細胞、骨細胞、幹細胞、間葉細胞、神経細胞、心臓細胞、含脂肪細胞、血管平滑筋細胞、心筋細胞、骨格筋細胞、β細胞、下垂体細胞、滑膜ライニング細胞、卵巣細胞、精巣細胞、線維芽細胞、B細胞、T細胞、網状赤血球、白血球、顆粒球、および腫瘍細胞からなる群から選択される、項目21に記載の方法。
(項目39)
機能的分泌性ポリペプチドが欠乏している対象を治療する方法であって、(a)少なくとも一部が前記機能的分泌性ポリペプチドをコードする少なくとも1つのmRNAと、(b)脂質ナノ粒子を含む移送ビヒクルと、を含む組成物を投与することを含み、前記組成物の投与後、前記mRNAは、標的細胞内で翻訳されて、投与の1時間を超えた後に少なくとも最小治療レベルで前記標的細胞内に前記機能的ポリペプチドを産生する、方法。
(項目40)
標的細胞内で機能的分泌性ポリペプチドを産生する方法であって、(a)少なくとも一部が前記機能的分泌性ポリペプチドをコードする少なくとも1つのmRNAと、(b)脂質ナノ粒子を含む移送ビヒクルと、を含む組成物を投与することを含み、前記組成物の投与後、前記mRNAは、標的細胞内で翻訳されて、投与の1時間を超えた後に少なくとも最小治療レベルで機能的分泌性ポリペプチドを産生する、方法。
上で論じられる特徴および多くの他の特徴ならびに本発明の付随する利点は、添付の実施例と併せて、本発明の以下の詳細な説明を参照することにより、より良好に理解されるであろう。本明細書に記載の様々な実施形態は相補的であり、本明細書に包含される教示を考慮して、当業者によって理解される様式でともに合わせられるか、または使用されてもよい。
本発明は、治療レベルの機能的分泌タンパク質の産生のために1つ以上の標的細胞にリポソーム移送ビヒクル中のmRNAを細胞内送達するための組成物および方法を提供する。
mRNA
l.,Molecular Therapy 16(11):1833−1840(2008)を参照されたい。本発明のmRNAの置換および修飾は、当業者に容易に既知の方法によって行われ得る。
移送担体
脂質ナノ粒子
特定の理論によって束縛されることを望むことなく、イミダゾールベースのカチオン性脂質ICEの融合性が、従来のカチオン性脂質と比較してより低いpKaを有するイミダゾール基によって促進されるエンドソーム破壊に関連していることが考えられる。次いで、エンドソーム破壊は、リポソーム膜の浸透圧膨張および破壊を促進し、その後、その中に装填される核酸(複数を含む)含有物の標的細胞へのトランスフェクションまたは細胞内放出が続く。
標的細胞
適用および投与
実施例
実施例1:ポリヌクレオチド組成物の静脈内送達を介するタンパク質産生デポー
ヒトエリスロポエチン(EPO)(配列番号3、図3)、ヒトα−ガラクトシダーゼ(GLA)(配列番号4、図4)、ヒトα−1抗トリプシン(A1AT)(配列番号5、図5)、およびヒト第IX因子(FIX)(配列番号6、図6)を、遺伝子をコードするプラスミドDNA鋳型からの生体外転写によって合成し、その後、5’キャップ構造(Cap1)(Fechter&Brownlee,J.Gen.Virology 86:1239−1249(2005))およびゲル電気泳動によって決定された約200ヌクレオチド長の3’ポリ(A)尾部を付加した。5’および3’非翻訳領域は、以下の実施例におけるそれぞれのmRNA産物において存在し、それぞれ、配列番号:1および2(図1および図2)によって定義される。
脂質ナノ粒子製剤
静脈内送達されたmRNA装填ナノ粒子を介して産生されたタンパク質の分析
注入プロトコル
分析のための臓器組織の単離
分析のための血清の単離
酵素結合イムノソルベントアッセイ(ELISA)分析
ウエスタンブロット分析
結果
1A.生体内ヒトEPOタンパク質産生結果
1B.生体内ヒトGLAタンパク質産生結果
1C.生体内ヒトFIXタンパク質産生結果
1D.生体内ヒトA1ATタンパク質産生結果
実施例2:ポリヌクレオチド組成物の肺送達を介するタンパク質産生デポー
注入プロトコル
結果
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