JP6145043B2 - 光遺伝的方法で使用するための光の上方変換 - Google Patents
光遺伝的方法で使用するための光の上方変換 Download PDFInfo
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Description
本願は、その開示がその全体で参照することにより本明細書に組み込まれる、2010年11月5日出願の米国仮出願第61/410,729号に対して優先権を請求する。
本発明の実践は、特に指示されない限り、当業者に周知である、分子生物学、微生物学、細胞生物学、生化学、核酸化学、免疫学、および生理学の従来の技法を採用する。そのような技法は、Molecular Cloning:A Laboratory Manual,second edition(Sambrook et al.,1989)and Molecular Cloning:A Laboratory Manual,third edition(Sambrook and Russel,2001),(jointly referred to herein as“Sambrook”);Current Protocols in Molecular Biology(F.M.Ausubel et al.,eds.,1987,including supplements through 2001);PCR :The Polymerase Chain Reaction,(Mullis et al.,eds.,1994);Harlow and Lane(1988),Antibodies,A Laboratory Manual,Cold Spring Harbor Publications,New York;Harlow and Lane(1999),Using Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY(jointly referred to herein as“Harlow and Lane”),Beaucage et al.eds.,Current Protocols in Nucleic Acid Chemistry,John Wiley & Sons,Inc.,New York,2000),Handbook of Experimental Immunology,4th edition(D.M.Weir & C.C.Blackwell,eds.,Blackwell Science Inc.,1987)、およびGene Transfer Vectors for Mammalian Cells(J.M.Miller & M.P.Calos,eds.,1987)等の文献で十分に説明されている。他の有用な参考文献は、HarrisonのPrinciples of Internal Medicine(McGraw Hill;J.Isseleacher et al.,eds.)、およびLanthanide Luminescence:Photophysical,Analytical and Biological Aspects(Springer−Verlag,Berlin,Heidelberg;Hanninen & Harma,eds.,2011)を含む。
本明細書で使用されるように、「赤外線」または「近赤外線」または「赤外光」または「近赤外光」とは、0.74μmにおける可視赤色光の公称境界から測定され、300μmにまで及ぶ、可視光の直上にあるスペクトル内の電磁放射線を指す。これらの波長は、約1から400THzの周波数範囲に対応する。具体的には、「近赤外線」または「近赤外光」はまた、水の吸収によって定義される、波長が0.75〜1.4μmとなる電磁放射線も指す。
材料科学では、ドーピングは、特定の鉄または原子種をホスト格子核構造に組み込んで、新しい有用な性質を伴うハイブリッド材料を生産するために一般的に使用されている。ナノ粒子を合成する時に、ドーピングは、粒子のサイズおよび形状だけでなく、近赤外線(NIR)励起を可視発光に変換する能力等の他の性質にも影響を及ぼすことができる。
本明細書では、中枢または末梢神経系のニューロンを選択的に過分極化または脱分極化するための光遺伝学ベースの組成物が提供される。光遺伝学とは、機能している無傷の生体系とペースを保つために必要とされる時間精度(ミリ秒の時間尺度)で、自由に行動しているほ乳類および他の動物の体内でさえも、生体組織の標的細胞内の特定の事象を制御するために使用される、遺伝的および光学的方法の組み合わせを指す。光遺伝学は、特定の標的機構の使用を通して細胞型分解能を維持しながら、ニューロン膜電位の時間的に正確な操作を可能にする、標的神経細胞の原形質膜への高速光応答性チャネルまたはポンプタンパク質の導入を必要とする。
本開示は、ほ乳類細胞の原形質膜への輸送を強化する、1つ以上のアミノ酸配列モチーフの追加によって、細胞において発現される光応答性オプシンタンパク質の修飾を提供する。進化的により単純な生物に由来する構成要素を有する、光応答性オプシンタンパク質は、ほ乳類細胞によって発現されない、または耐えられなくてもよく、あるいはほ乳類細胞において高レベルで発現された時に低下した細胞内局在性を示してもよい。その結果として、いくつかの実施形態では、細胞において発現される光応答性オプシンタンパク質は、シグナルペプチド、小胞体(ER)移行シグナル、膜輸送シグナル、および/またはN末端ゴルジ移行シグナルから成る群より選択される、1つ以上の1つ以上のアミノ酸配列モチーフに融合させることができる。ほ乳類細胞の原形質膜への光応答性オプシンタンパク質輸送を強化する、1つ以上のアミノ酸配列モチーフは、光応答性オプシンタンパク質のN末端、C末端、またはNおよびC末端の両方に融合させることができる。随意で、光応答性オプシンタンパク質および1つ以上のアミノ酸配列モチーフは、リンカーによって分離されてもよい。いくつかの実施形態では、光応答性オプシンタンパク質は、細胞原形質膜へのタンパク質の輸送を強化する輸送シグナル(ts)の追加によって修飾することができる。いくつかの実施形態では、輸送シグナルは、ヒト内向き整流カリウムチャネルKir2.1のアミノ酸配列から導出することができる。他の実施形態では、輸送シグナルは、アミノ酸配列KSRITSEGEYIPLDQIDINVを含むことができる。
いくつかの態様では、本明細書で説明される光応答性オプシンタンパク質は、光応答性塩素ポンプである。本明細書で提供される方法のいくつかの態様では、光応答性塩素ポンプのハロロドプシン族の1つ以上の構成要素が、中枢および末梢神経系のニューロンの原形質膜上で発現される。
いくつかの態様では、本明細書で説明される光応答性オプシンタンパク質は、光応答性プロトンポンプである。本明細書で提供される組成物および方法のいくつかの態様では、1つ以上の光応答性プロトンポンプが、中枢または末梢神経系のニューロンの原形質膜上で発現される。
いくつかの態様では、本明細書で説明される光応答性オプシンタンパク質は、光活性化カチオンチャネルタンパク質である。本明細書で提供される方法のいくつかの態様では、1つ以上の光活性化カチオンチャネルは、中枢または末梢神経系の神経細胞の原形質膜上で発現することができる。
他の実施形態では、光活性化カチオンチャネルタンパク質は、タンパク質のレチナール結合ポケットの全体を通した主要位置に特定のアミノ酸置換を有することができる、段階機能オプシン(SFO)タンパク質または安定化段階機能オプシン(SSFO)タンパク質となり得る。いくつかの実施形態では、SFOタンパク質は、配列番号5のアミノ酸残基C128に突然変異を有することができる。他の実施形態では、SFOタンパク質は、配列番号5の中にC128A突然変異を有する。他の実施形態では、SFOタンパク質は、配列番号5の中にC128S突然変異を有する。別の実施形態では、SFOタンパク質は、配列番号5の中にC128T突然変異を有する。いくつかの実施形態では、SFOタンパク質は、配列番号6で示される配列と少なくとも約90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一である、アミノ酸配列を含むことができる。
他の実施形態では、光活性化カチオンチャネルタンパク質は、ボルボックス・カルテリのVChR1タンパク質およびコナミドリムシのChR1タンパク質に由来するC1V1キメラタンパク質となり得て、タンパク質は、ChR1の第1および第2の膜貫通ヘリックスによって置換される、少なくとも第1および第2の膜貫通ヘリックスを有する、VChR1のアミノ酸配列を含み、光に応答し、細胞が光で照射された時に、細胞内の脱分極電流を仲介することが可能である。いくつかの実施形態では、C1V1タンパク質はさらに、キメラ光応答性タンパク質の第2および第3の膜貫通ヘリックスの間に位置する、細胞内ループドメイン内に置換を含むことができ、細胞内ループドメインの少なくとも一部分は、ChR1の対応する部分によって置換される。別の実施形態では、C1V1キメラタンパク質の細胞内ループドメインの一部分は、ChR1のアミノ酸残基A145にまで及ぶ、ChR1からの対応する部分と置換することができる。他の実施形態では、C1V1キメラタンパク質はさらに、キメラ光応答性タンパク質の第3の膜貫通ヘリックス内に置換を含むことができ、第3の膜貫通ヘリックスの少なくとも一部分は、ChR1の対応する配列によって置換される。さらに別の実施形態では、C1V1キメラタンパク質の細胞内ループドメインの一部分は、ChR1のアミノ酸残基W163にまで及ぶ、ChR1からの対応する部分と置換することができる。他の実施形態では、C1V1キメラタンパク質は、配列番号8で示される配列と少なくとも約90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一である、アミノ酸配列を含むことができる。
いくつかの態様では、本発明は、置換または変異アミノ酸配列を含む、ポリペプチドを含むことができ、変異ポリペプチドは、前駆体C1V1キメラポリペプチドの特徴的な光応答性質を保持するが、また、いくつかの特定の態様では、改変した性質を保有してもよい。例えば、本明細書で説明される変異光活性化C1V1キメラタンパク質は、動物細胞内または動物細胞原形質膜上の両方での増加したレベルの発現、光の異なる波長、具体的には赤色光に暴露された時の改変した応答性、および/または特質の組み合わせを示すことができ、それにより、キメラC1V1ポリペプチドは、低い脱感作、高速非活性化、他の光活性化カチオンチャネルを用いた最低限の相互活性化のための低い紫色光活性化、および/または動物細胞での強力な発現という性質を保有する。
本開示はまた、本明細書で説明される光応答性オプシンタンパク質をコードするヌクレオチド配列を含む、ポリヌクレオチドも提供する。いくつかの実施形態では、ポリヌクレオチドは、発現カセットを含む。いくつかの実施形態では、ポリヌクレオチドは、上記の核酸を含むベクターである。いくつかの実施形態では、本開示の光活性化タンパク質をコードする核酸は、プロモータに動作可能に結合される。プロモータは、当技術分野で周知である。宿主細胞で機能する任意のプロモータを、本開示の光応答性オプシンタンパク質および/またはその任意の変異形の発現に使用することができる。一実施形態では、光応答性オプシンタンパク質の発現を駆動するために使用されるプロモータは、運動ニューロンに特有であるプロモータである。別の実施形態では、光応答性オプシンタンパク質の発現を駆動するために使用されるプロモータは、中枢神経系ニューロンに特有であるプロモータである。他の実施形態では、プロモータは、交感および/または副交感神経系の両方のニューロンにおける光応答性オプシンタンパク質の発現を駆動することが可能である。特定の動物細胞における光応答性オプシンタンパク質またはその変異形の発現を駆動するのに有用である、開始制御領域またはプロモータは、多数あり、当業者に周知である。これらの核酸を駆動することが可能な事実上いかなるプロモータも使用することができる。運動ニューロン特有の遺伝子の例は、例えば、Kudo,et al.,Human Mol.Genetics,2010,19(16):3233−3253で見出すことができ、その内容は、それらの全体で参照することにより本明細書に組み込まれる。いくつかの実施形態では、光活性化タンパク質の発現を駆動するために使用されるプロモータは、中枢および末梢神経系の両方のニューロンにおいて導入遺伝子の堅調な発現を駆動することが可能である、Thy1プロモータとなり得る(例えば、Llewellyn,et al.,2010,Nat.Med.,16(10):1161−1166を参照)。他の実施形態では、光応答性オプシンタンパク質の発現を駆動するために使用されるプロモータは、EF1αプロモータ、サイトメガロウイルス(CMV)プロモータ、CAGプロモータ、シナプシンプロモータ、あるいはほ乳類の末梢および/または中枢神経系ニューロンにおいて光応答性オプシンタンパク質の発現を駆動することが可能な任意の他の普遍的プロモータとなり得る。
いくつかの態様では、本明細書で開示される光応答性オプシンタンパク質をコードするポリヌクレオチド(例えば、AAV1ベクター)は、定位固定注射(例えば、そのそれぞれの内容が、それらの全体で参照することにより本明細書に組み込まれる、Stein et al.,J.Virol.,1999,73:34243429;Davidson et al.,Proc.Nat.Acad.Sci.U.S.A.,2000,97:3428−3432;Davidson et al.,Nat.Genet.,1993,3:219−223;およびAlisky & Davidson,Hum.Gene Ther.,2000,11:2315−2329を参照)または蛍光透視法によるもの等の当技術分野で公知の神経外科技法を使用した、針、カテーテル、または関連デバイスを用いて、中枢または末梢神経系のニューロンに直接送達することができる。いくつかの実施形態では、本明細書で開示される光応答性オプシンタンパク質をコードするポリヌクレオチド(例えば、AAV1ベクター)は、脊髄神経(頸部脊髄神経、胸部脊髄神経、腰椎神経、仙骨脊髄神経、および/または尾骨脊髄神経)のうちのいずれか1つへの注射によって、末梢神経系のニューロンに送達することができる。
赤外線(IR)または近赤外線(NIR)スペクトル内の波長を有する電磁放射線源を産生することが可能である、任意のデバイスが、本明細書で説明されるランタニドをドープしたナノ粒子と組み合わせて、ニューロンの表面上で発現される1つ以上の光応答性タンパク質を活性化するために使用されてもよい。IRまたはNIR源は、光刺激を脳の特定の標的領域に提供するように構成することができる。IRまたはNIR源は、加えて、連続IRあるいはNIR電磁放射線および/またはパルスIRあるいはNIR電磁放射線を提供することができ、所定のパルス系列でIRまたはNIR電磁放射線を提供するようにプログラム可能であってもよい。
本発明の方法
本明細書では、神経細胞に近接して複数のランタニドをドープしたナノ粒子を配置することと、複数のナノ粒子を、赤外線(IR)または近赤外線(NIR)スペクトル内の電磁放射線に暴露させることであって、IRまたはNIRスペクトル内の電磁放射線は、ナノ粒子によって可視スペクトル内の光に上方変換され、光応答性オプシンが、神経細胞の原形質膜上で発現され、可視スペクトル内の光によるオプシンの活性化は、原形質膜の脱分極を誘発する、暴露させることとを含む、個体の神経細胞の原形質膜を脱分極化する方法が提供される。
本明細書では、神経細胞に近接して複数のランタニドをドープしたナノ粒子を配置することと、複数のナノ粒子を、赤外線(IR)または近赤外線(NIR)スペクトル内の電磁放射線に暴露させることであって、IRまたはNIRスペクトル内の電磁放射線は、ナノ粒子によって可視スペクトル内の光に上方変換され、光応答性オプシンが、神経細胞の原形質膜上で発現され、可視スペクトル内の光によるオプシンの活性化は、原形質膜の過分極を誘発する、暴露させることとを含む、個体の神経細胞の原形質膜を過分極化する方法が提供される。
また、本明細書では、光応答性オプシンタンパク質(本明細書で説明される光応答性オプシンタンパク質のうちのいずれか等)をコードするポリヌクレオチドと、中枢および/または末梢神経系の1つ以上のニューロンの膜分極状態を改変するために本明細書で開示される方法のうちのいずれかで使用するためのランタニドをドープしたナノ粒子とを含む、キットが提供される。いくつかの実施形態では、キットはさらに、赤外線または近赤外線電磁放射線源を備える。他の実施形態では、キットはさらに、本明細書で説明されるポリヌクレオチドおよびランタニドをドープしたナノ粒子を使用するための説明書を備える。なおも他の実施形態では、本明細書で説明されるランタニドをドープしたナノ粒子は、生体適合性材料(上記で説明される生体適合性材料のうちのいずれか等)に埋め込まれる、および/または閉じ込められる。
例示的実施形態
側坐核(NAc)は、腹側線条体の主要部を形成するニューロンの集合である。NAcは、報酬、喜び、笑い、依存症、攻撃、恐怖、およびプラセボ効果と関連付けられる複雑なほ乳類の挙動において重要な役割を果たすと考えられている。NAc内のコリン作動性介在ニューロンは、局所神経細胞集団の1%未満を構成するが、それでもなお、NAcの全体を通して突出し、その既知のコリン作動性入力のみを提供する。この実施例では、ランタニドをドープしたナノ粒子と組み合わせて光応答性塩素ポンプタンパク質を使用する、光遺伝的アプローチは、高い時間分解能および高い細胞型特性の両方を伴って、これらの細胞における活動電位発火を阻止するために使用される。特異的にコリン作動性介在ニューロンにおいて微生物オプシン遺伝子を発現するために、Creリコンビナーゼを発現する遺伝子導入マウス系が、コリンアセチルトランスフェラーゼ(ChAT)プロモータの下で採用される。強化黄色蛍光タンパク質(eYFP)のためのコード配列を伴ってフレーム内で融合された、黄色光ゲート第3世代塩素ポンプハロロドプシン(eNpHR3.0)遺伝子を持つ、Cre誘発性アデノ随伴ウイルス(AAV)ベクターが、定位固定的に注射される。
Claims (15)
- 個体の神経細胞の原形質膜を脱分極化または過分極化する方法に用いるための、ランタニドをドープした複数のナノ粒子と光応答性オプシンとを含む製造品であって、
前記複数のナノ粒子は、赤外線または近赤外線スペクトル内の電磁放射線に曝露されると、前記赤外線または近赤外線スペクトル内の前記電磁放射線が、前記ナノ粒子によって可視スペクトル内の光に上方変換されるものであり、前記光応答性オプシンは、前記神経細胞の原形質膜上で発現され、前記可視スペクトル内の光によるオプシンの活性化が、前記原形質膜の脱分極または過分極を誘導するものであり、
前記光応答性オプシンが、配列番号6、7、8、9、10および11のいずれか一に示すアミノ酸配列と少なくとも90%のアミノ酸配列同一性があるか、あるいは配列番号2および3のいずれか一に示すアミノ酸配列と少なくとも95%のアミノ酸配列同一性があるアミノ酸配列を含み、光応答性オプシンのアミノ酸配列が配列番号6、7、8、9、10および11のいずれかである場合には前記原形質膜が脱分極化され、光応答性オプシンのアミノ酸配列が配列番号2または3である場合には前記原形質膜が過分極化される、製造品。 - 個体の神経細胞の原形質膜を脱分極化または過分極化する方法に用いるための、ランタニドをドープした複数のナノ粒子と光応答性オプシンをコードするポリヌクレオチドとを含む製造品であって、
前記光応答性タンパク質は、個体の神経細胞の原形質膜上で発現され、前記オプシンが、光で照明されたときに神経細胞の膜の脱分極または過分極を誘導することが可能であり、
前記ランタニドをドープした複数のナノ粒子は前記神経細胞に近接しており、
前記複数のナノ粒子は、赤外線または近赤外線スペクトル内の電磁放射線に曝露されると、前記赤外線または近赤外線スペクトル内の前記電磁放射線が、可視スペクトル内の光に上方変換され、前記可視スペクトル内の光によるオプシンの活性化が、前記原形質膜の脱分極または過分極を誘導するものであり、
前記光応答性オプシンが、配列番号6、7、8、9、10および11のいずれか一に示すアミノ酸配列と少なくとも90%のアミノ酸配列同一性があるか、あるいは配列番号2および3のいずれか一に示すアミノ酸配列と少なくとも95%のアミノ酸配列同一性があるアミノ酸配列を含み、光応答性オプシンのアミノ酸配列が配列番号6、7、8、9、10および11のいずれかである場合には前記原形質膜が脱分極化され、光応答性オプシンのアミノ酸配列が配列番号2または3である場合には前記原形質膜が過分極化される、製造品。 - 前記光応答性オプシンが、配列番号6、7、8、9、10および11のいずれか一に示すアミノ酸配列と少なくとも95%のアミノ酸配列同一性があるアミノ酸配列を含む、請求項1または2に記載の製造品。
- 前記光応答性オプシンが、配列番号6、7、8、9、10および11のいずれか一に示すアミノ酸配列と少なくとも98%のアミノ酸配列同一性があるアミノ酸配列を含む、請求項1または2に記載の製造品。
- 前記ランタニドをドープしたナノ粒子が、ランタン、セリウム、プラセオジム、ネオジム、プロメチウム、サマリウム、ユーロピウム、ガドリニウム、テルビウム、ジスプロシウム、ホルミウム、エルビウム、ツリウム、イッテルビウム、およびルテチウムからなる群より選択されるランタニド金属を含む、請求項1から4のいずれか一項に記載の製造品。
- 前記ランタニドをドープしたナノ粒子が、NaYF4:Yb/X/Gdを含み、Xが、Er、Tm、またはEr/Tmである、請求項1から5のいずれか一項に記載の製造品。
- 前記赤外線または近赤外線スペクトル内の電磁放射線が、約450nm〜約550nmの波長を有する光に上方変換される、請求項1から6のいずれか一項に記載の製造品。
- 前記赤外線または近赤外線スペクトル内の電磁放射線が、赤色、黄色または琥珀色の光に対応する波長を有する光に上方変換される、請求項1から6のいずれか一項に記載の製造品。
- 前記赤外線または近赤外線スペクトル内の電磁放射線が、緑色または青色の光に対応する波長を有する光に上方変換される、請求項1から6のいずれか一項に記載の製造品。
- 前記個体が、ヒト以外の動物である、請求項1から9のいずれか一項に記載の製造品。
- 前記個体が、ヒトである、請求項1から9のいずれか一項に記載の製造品。
- 前記神経細胞が、中枢神経系内の神経細胞である、請求項1から11のいずれか一項に記載の製造品。
- 前記神経細胞が、末梢神経系内の神経細胞である、請求項1から11のいずれか一項に記載の製造品。
- ヒトまたはヒト以外の動物の頭蓋骨が外科的に薄くされ、赤外線または近赤外線の源が、薄くなった頭蓋骨領域上に直接配置される、請求項10または11に記載の製造品。
- 前記神経細胞が、中枢神経系または末梢神経系内の神経細胞である、請求項1から14のいずれか一項に記載の製造品。
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WO2012061684A1 (en) | 2012-05-10 |
CA2817175A1 (en) | 2012-05-10 |
CN106422081B (zh) | 2019-06-21 |
US20140148880A1 (en) | 2014-05-29 |
JP2017170163A (ja) | 2017-09-28 |
EP2635341A4 (en) | 2016-05-25 |
JP2014502177A (ja) | 2014-01-30 |
US20190217118A1 (en) | 2019-07-18 |
JP6505158B2 (ja) | 2019-04-24 |
AU2016202003A1 (en) | 2016-04-21 |
EP2635341B1 (en) | 2018-08-08 |
EP2635341A1 (en) | 2013-09-11 |
US20160317658A1 (en) | 2016-11-03 |
CN103313752B (zh) | 2016-10-19 |
AU2016202003B2 (en) | 2018-06-14 |
US9522288B2 (en) | 2016-12-20 |
CN110215614A (zh) | 2019-09-10 |
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