JP2022512739A - 操作された長鎖散在反復エレメント(line)トランスポゾンおよびそれらの使用方法 - Google Patents
操作された長鎖散在反復エレメント(line)トランスポゾンおよびそれらの使用方法 Download PDFInfo
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Abstract
Description
本願は、これによりその全体が参照により本明細書に組み込まれる、2018年10月19日に出願した米国特許出願第62/748,227号に基づく利益および優先権を主張するものである。
本発明は、米国国立科学財団により与えられた助成0950983の下、政府支援を受けてなされたものである。米国政府は本発明に一定の権利を有する。
17,183バイトのサイズを有する「UTSB_18_47_PCT_ST25.txt」という名称のテキストファイルとして提出した配列表は、連邦規則集第37巻1条52項(e)(5)に従ってこれにより参照により本明細書に組み込まれる。
本発明は、一般に、ゲノム修飾のための組成物および方法に関する。
ゲノム編集技術は、がん、遺伝障害およびHIV/AIDSを含むがこれらに限定されない、様々な疾患および障害の治療に役立つ可能性がある。体細胞のゲノム編集は、治療法の開発の有望な分野であり、複合酵素編集ツールCRISPR-Cas9が、ヒト胚の生殖細胞系列からヒトβグロビン(HBB)遺伝子を除去するために使用された(Otieno, (2015), J Clin Res Bioeth 6:253. doi: 10.4172/2155-9627.1000253)。しかし、歴史的に、遺伝子編集技術の臨床応用は、数ある懸念の中でも特に、編集事象の低い頻度、高いオフターゲット事象、またはこれらの組合せにより、制限されてきた。
操作されたトランスポゾンおよびそれらの使用方法が提供される。トランスポゾンは代表的には、RNA成分およびタンパク質成分を含む。RNA成分は、例えば、DNA標的化配列と、1つまたは複数のタンパク質結合モチーフと、DNA標的部位に組み込まれる目的の核酸配列とを含み得る。DNA標的化配列、タンパク質結合モチーフ、および目的の配列は代表的には、制限酵素様エンドヌクレアーゼ長鎖散在反復(RLE LINE)エレメントタンパク質に由来するタンパク質成分に結合し、逆転写され、生じたcDNAが、例えば細胞ゲノム内の、DNAのDNA標的部位に組み込まれるように、作動可能に連結されている。目的の配列は、例えば、遺伝子もしくはその断片、または機能性核酸をコードすることができる。
I.定義
本明細書で使用される場合、用語「担体」または「賦形剤」は、1つまたは複数の活性成分と組み合わせられる有機または無機成分である、製剤中の天然または合成不活性成分を指す。
II.操作されたトランスポゾン
A.操作されたトランスポゾンの構造
1.RNA成分
2.タンパク質成分
B.RNAおよびタンパク質成分の配列源
1.親レトロトランスポゾン
2.DNA結合ドメイン源
3.導入遺伝子源
a.目的のポリペプチド
b.機能性核酸
c.発現エレメント
C.設計上の考慮事項
1.4方向分岐型DNA中間体
a.R2タンパク質は、一般的なホリデイジャンクションリゾルバーゼではなく、リゾルバーゼ様反応においてそれ自体の組込み中間体を切断する。
b.R2Bm組込みの新モデル
c.異なる切断位置のずれを有するLINEへのR2モデルの外挿
d.組込みを維持するための設計上の考慮事項
2.リンカー領域
a.リンカーの主な役割はエレメントRNAを結合することであるように見えない。
b.リンカーは組込み反応の前半の間にRLEおよびRTに核酸を提示する。
c.リンカー領域は組込み反応の後半の鍵である。
d.APE LINEとのおよびPrp8との構造的および機能的接続
e.組込みを維持するための設計上の考慮事項
III.使用方法
A.ベクターおよび宿主細胞
B.細胞ゲノムの編集方法
1.ex vivo遺伝子治療
2.in vivo遺伝子治療
a.医薬製剤
b.投与方法
c.粘膜および肺内投与のための好ましい製剤
C.処置される疾患
(実施例1)
R2タンパク質は非特異的線状DNAよりも非特異的4方向ジャンクションDNAに優先的に結合する。
材料および方法
タンパク質精製
核酸調製
R2Bm反応および分析
(実施例2)
3’PBM RNAではなく5’PBM RNAは、非特異的4方向DNAジャンクションへの結合を阻害する。
(実施例3)
R2タンパク質は非特異的4方向ジャンクションDNAを分解しない。
(実施例4)
線状標的DNAおよびTPRT生成物は第2鎖切断の不良な基質である。
(実施例5)
特定の4方向ジャンクションがR2タンパク質により切断される。
(実施例6)
第2鎖DNA切断のさらなる探究。
(実施例7)
第2鎖切断はdNTPの存在下で第2鎖合成に至る。
(実施例8)
すでに切断されているDNA構築物における第2鎖合成。
(実施例9)
HINALPおよびCCHCモチーフのコア残基の変異は、標的DNA結合に影響を与え、DNA切断特異性の喪失をもたらす。
材料および方法
変異
タンパク質および核酸調製
R2Bm反応および分析
結果
(実施例10)
推定αフィンガーの変異は、DNA結合、特に、特定の分岐型組込み中間体アナログへのDNA結合に影響を与える。
(実施例11)
推定αフィンガーの変異は第1鎖DNA切断を低減させる
(実施例12)
推定αフィンガーの変異は第1鎖cDNA合成を低減させる
(実施例13)
推定αフィンガーの変異は第2鎖DNA切断に影響を与える
(実施例14)
推定αフィンガーの変異は第2鎖合成に影響を与える
(実施例15)
ジンクナックル領域の残基の変異は標的DNA切断および第2鎖合成に影響を与える
「++」:+30%およびそれより高度
「+」:+15%~30%
「WT」:WT活性の15%~-15%:機能的にWT
「-」:-15%~-30%:わずかな低減
「--」:-30%~-50%:大幅な低減
「---」:-50%~75%:著しい低減
「φ」:75%またはそれより高度:機能的に無効
Claims (36)
- DNA標的化配列と、1つまたは複数のタンパク質結合モチーフ(PBM)と、DNA標的部位に組み込まれる目的の核酸配列とを含むRNA成分であって、前記DNA標的化配列、前記タンパク質結合モチーフ、および目的の配列は、親長鎖散在反復(LINE)エレメントタンパク質に由来するタンパク質成分に結合し、cDNAに逆転写され得、前記cDNAがDNAの前記DNA標的部位に組み込まれ得るように、作動可能に連結されている、RNA成分。
- 前記タンパク質成分が、RNA結合ドメイン、リンカードメイン、逆転写酵素、DNAエンドヌクレアーゼのうちの1つまたは複数を含み、前記1つまたは複数のタンパク質結合モチーフが、前記RNA成分を、前記タンパク質成分の前記RNA結合ドメイン、リンカードメイン、逆転写酵素、DNAエンドヌクレアーゼ、またはこれらの組合せに結合させる、請求項1に記載のRNA成分。
- 親LINEもしくはSINE骨格からのまたはそれに由来するエレメントを含み、RNA成分の前記目的の核酸配列が、前記LINEまたはSINEとは異種である;
タンパク質成分が、親LINEからのまたはそれに由来するエレメントを含む;あるいは
それらの組合せである、
請求項1または2に記載のRNA成分。 - 前記DNA標的化配列が、前記親LINEまたはSINEとは異種である、請求項1~3のいずれか一項に記載のRNA成分。
- 前記目的の配列が、遺伝子、遺伝子の断片、または機能性核酸をコードする、請求項1~4のいずれか一項に記載のRNA成分。
- 親LINEもしくはSINEエレメントからのまたはそれに由来する3’PBM配列を含む、請求項1~5のいずれか一項に記載のRNA成分。
- CRISPR/Casトレーサー配列、CRISPR/Casガイド配列、またはこれらの組合せを含む、請求項1~6のいずれか一項に記載のRNA成分。
- 前記親LINEもしくはSINEエレメントからのまたはそれに由来する5’PBM配列を含む、請求項1~7のいずれか一項に記載のRNA成分。
- 前記5’PBMが、非機能性IRES配列を含む、請求項8に記載のRNA成分。
- リボザイムをさらに含む、請求項1~9のいずれか一項に記載のRNA成分。
- 前記リボザイムが、デルタ肝炎ウイルス様リボザイムである、請求項10に記載のRNA成分。
- 前記親LINEまたはSINEが、制限酵素様エンドヌクレアーゼ(RLE)LINEである、請求項2~10のいずれか一項に記載のRNA成分。
- 前記RLE LINEが、R2 LINEである、請求項10に記載のRNA成分。
- 前記RNA成分の前記親LINEまたはSINE骨格、および前記タンパク質成分の前記親LINE骨格が、同じLINEであるか、ならびに/または前記SINEが、前記LINEに由来するか、もしくは前記LINEの祖先である、請求項3~13のいずれか一項に記載のRNA成分。
- DNA結合ドメイン、RNA結合ドメイン、逆転写酵素、リンカードメインおよびエンドヌクレアーゼを含むタンパク質成分であって、前記DNA結合ドメイン、RNA結合ドメイン、逆転写酵素、リンカードメインおよびエンドヌクレアーゼは、DNA標的部位においてRNA成分およびDNAに結合し得、前記RNA成分からcDNAへの逆転写、および前記DNA標的部位において、前記DNAへの前記cDNAの組込みを助長し得るように、作動可能に連結されている、タンパク質成分。
- 前記RNA成分が、DNA標的化配列と、1つまたは複数のタンパク質結合モチーフと、前記DNA標的部位に組み込まれる目的の核酸配列とを含む、請求項15に記載のタンパク質成分。
- 前記RNA成分が、親LINEもしくはSINE骨格からのまたはそれに由来するエレメントを含み、RNA成分の前記目的の核酸配列が、前記LINEまたはSINEとは異種である;
タンパク質成分が、親LINEからのまたはそれに由来するエレメントを含む;あるいは
それらの組合せである、
請求項15または16に記載のタンパク質成分。 - 前記DNA結合ドメインが、親LINE DNA結合ドメインと比較して変異している、請求項15~17のいずれか一項に記載のタンパク質成分。
- 前記DNA結合ドメインが、前記親LINE DNA結合ドメインと比較して代替DNA結合ドメインで置換されている、請求項15~17のいずれか一項に記載のタンパク質成分。
- 前記DNA結合ドメインが、別のDNA結合タンパク質からのDNA結合ドメインである、請求項19に記載のタンパク質成分。
- 前記DNA結合ドメインが、ヘリックスターンヘリックス、ジンクフィンガー、ロイシンジッパー、ウイングドヘリックス、ウイングドヘリックスターンヘリックス、ヘリックスループヘリックス、HMGボックス、Wor3ドメイン、OBフォールドドメイン、免疫グロブリンフォールド、B3ドメイン、TALエフェクター、またはRNAガイドドメインのうちの1つまたは複数を含む、請求項19または20に記載のタンパク質成分。
- 前記RNA結合ドメイン、逆転写酵素、リンカードメインおよびエンドヌクレアーゼのうちの1つまたは複数の配列が、前記親LINEエレメントタンパク質の配列と同じである、または前記親LINEエレメントタンパク質と比較して前記RNA成分に対する結合もしくは酵素活性を改善するように変異している、請求項15~22のいずれか一項に記載のタンパク質成分。
- 前記親LINEまたはSINEが、制限酵素様エンドヌクレアーゼ(RLE)LINEである、請求項17~22のいずれか一項に記載のタンパク質成分。
- 前記RLE LINEが、R2 LINEである、請求項23に記載のタンパク質成分。
- 前記RNA成分の前記親LINEまたはSINE骨格、および前記タンパク質成分の前記親LINE骨格が、同じLINEであるか、ならびに/または前記SINEが、前記LINEに由来するか、もしくは前記LINEの祖先である、請求項17~24のいずれか一項に記載のタンパク質成分。
- 請求項1~14のいずれか一項に記載のRNA成分をコードするベクター。
- 請求項15~25のいずれか一項に記載のタンパク質成分をコードするベクター。
- 請求項1~14のいずれか一項に記載のRNA成分と、請求項15~25のいずれか一項に記載のタンパク質成分とを含む操作されたトランスポゾン。
- 前記DNA標的部位での組込み反応中に生産的な4方向ジャンクションが形成される、請求項28に記載のトランスポゾン。
- 請求項1~14のいずれか一項に記載のRNA成分、請求項15~25のいずれか一項に記載のタンパク質成分、請求項26に記載のベクター、請求項27に記載のベクター、請求項28または29に記載の操作されたトランスポゾン、またはこれらの任意の組合せを含む、医薬組成物。
- 1つまたは複数の細胞のゲノムに目的の核酸配列を導入する方法であって、前記1つまたは複数の細胞を、(i)請求項15~25のいずれか一項に記載のタンパク質成分もしくは請求項17に記載のベクターと組み合わせて、請求項1~14のいずれか一項に記載のRNA成分もしくは請求項26に記載のベクターと、または(ii)請求項28もしくは29に記載の操作されたトランスポゾンと接触させるステップを含む方法。
- 前記細胞をin vitroで接触させる、請求項31に記載の方法。
- 次いで前記細胞が対象に導入される、請求項32に記載の方法。
- 前記細胞をin vivoで接触させる、請求項31に記載の方法。
- 前記細胞における前記目的の核酸配列の発現が、疾患もしくは障害の1つもしくは複数の症状、または疾患もしくは障害の根底にある分子経路を改善する、請求項31~34のいずれか一項に記載の方法。
- 有効数の細胞が、それを必要とする対象を処置するために修飾される、請求項35に記載の方法。
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US4452775A (en) | 1982-12-03 | 1984-06-05 | Syntex (U.S.A.) Inc. | Cholesterol matrix delivery system for sustained release of macromolecules |
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