JP2021503960A - 神経疾患のための組成物および方法 - Google Patents
神経疾患のための組成物および方法 Download PDFInfo
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Abstract
Description
米国特許法第119条(e)に従って、本出願は、2017年11月27日に出願された米国仮特許出願第62/590,911号および2018年4月19日に出願された米国仮特許出願第62/659,911号の出願日に対する優先権を主張するものであり、これらの全開示は参照により本明細書に組み込まれる。
本出願に関連する配列表は、ハードコピーの代わりにテキスト形式で提供され、参照により本明細書に組み込まれる。配列表を含むテキストファイルの名称は、SWCH_012_04WO_ST25.txtである。このテキストファイルは178kbであり、2018年11月27日に作成され、EFS−Webを介して電子的に提出される。
操作された受容体、操作された受容体をコードするポリヌクレオチド、および操作された受容体をコードするポリヌクレオチドを含む遺伝子治療ベクターを使用して、細胞の活性を調節するための組成物および方法が提供される。これらの組成物および方法は、例えば、疾患の治療または神経回路の研究における、ニューロンの活性の調節に特定の用途を見出す。
操作されたリガンド依存性イオンチャネル(LGIC)受容体、操作されたLGIC受容体をコードするポリヌクレオチド、および操作された受容体をコードするポリヌクレオチドを含む遺伝子治療ベクターを使用して、細胞の活性を調節するための組成物および方法が提供される。これらの組成物および方法は、例えば、疾患の治療または神経回路の研究における、ニューロンの活性の調節に特定の用途を見出す。加えて、本発明の方法の実施において用途を見出される試薬、デバイス、およびそのキットが提供される。
本明細書および添付の特許請求の範囲で使用される場合、単数形の「a」、「an」および「the」は、趣旨が明らかにそうではないと指示しない限り、複数への言及を含む。したがって、例えば、「細胞(a cell)」への言及は、そのような細胞の複数形を含み、「ペプチド(the peptide)」への言及は、1つ以上のペプチドおよびその等価物、例えば、当業者に既知のポリペプチド等への言及を含む。
本開示は、操作された受容体、操作された受容体変異体、およびそれらの使用方法に関する。本明細書で使用される「受容体」という用語は、細胞の表面に位置し、細胞へのシグナル伝達および/または細胞からのシグナル伝達を媒介することができる任意のタンパク質を指す。「操作された受容体」という用語は、対応する親受容体と物理的および/または機能的に異なるように実験的に改変された受容体を指すために本明細書で使用される。いくつかの実施形態において、親受容体は、野生型受容体である。用語「野生型受容体」は、本明細書において、天然に見られるタンパク質のポリペプチド配列と同一であるポリペプチド配列を有する受容体を指すために使用される。野生型受容体としては、ヒトにおいて天然に生じる受容体、ならびに他の真核生物、例えば、原生生物、真菌、植物または動物、例えば、酵母、昆虫、線虫、海綿動物、哺乳動物、非哺乳動物の脊椎動物において天然に生じるオルソログが挙げられる。他の実施形態において、親受容体は、非天然受容体であり、すなわち、それは、天然には存在しない受容体、例えば、野生型受容体から操作された受容体である。例えば、親受容体は、第2の野生型受容体からの1つ以上のサブユニットとともに、1つの野生型受容体からの1つ以上のサブユニットを含む操作された受容体であり得る。したがって、得られるタンパク質は、2つ以上の野生型受容体からのサブユニットから構成される。本開示の操作された受容体としては、例えば、親受容体、親受容体変異体、およびスイッチ受容体が挙げられる。
「結合剤」または「剤」という用語は、本明細書において互換的に使用され、哺乳動物細胞上で既知の作用機構を有する外因性薬物または化合物を指す(例えば、受容体のアゴニスト、アンタゴニスト、または調節因子として機能することが既知である)。結合剤は、タンパク質、脂質、核酸、および/または小分子を含むことができる。いくつかの実施形態において、結合剤としては、特定の疾患(例えば、神経疾患)の治療における臨床使用のために米国食品医薬品局(FDA)によって承認された薬物または化合物が挙げられる。いくつかの実施形態において、結合剤は、臨床使用のためにFDAによって承認されていないが、1つ以上の臨床試験において試験されている、1つ以上の臨床試験において現在試験されている、および/または1つ以上の臨床試験において試験されることが予想される薬物または化合物を含む。いくつかの実施形態において、結合剤としては、臨床使用のためにFDAによって承認されていないが、実験室での研究において日常的に使用される薬物または化合物が挙げられる。いくつかの実施形態において、結合剤は、前述の剤のうちの1つのアナログである。特定の実施形態において、結合剤は、表2〜9の剤のいずれか1つから選択される。いくつかのそのような実施形態において、結合剤は、AZD0328、ABT−126、AQW−051、カンナビジオール、シランセトロン、PH−399733、ファシニクリン/RG3487/MEM−3454、およびTC−5619/AT−101からなる群から選択される。特定の実施形態において、結合剤は、シランセトロンのアナログであり、例えば、そのRまたはSエナンチオマーである化学式2〜7のうちの1つにより記載されているようなものである:
様々な例示的な実施形態において、本開示は、部分的に、ポリヌクレオチド、LGICを含む操作された受容体ポリペプチドをコードするポリヌクレオチド、ならびにそのサブユニットおよび変異タンパク質、ならびに融合ポリペプチド、ウイルスベクターポリヌクレオチド、ならびにそれらを含む組成物を企図する。
本開示のいくつかの態様において、核酸分子、すなわち、操作された受容体をコードするポリヌクレオチドが対象に送達される。ある場合には、操作された受容体をコードする核酸分子は、ベクターによって対象に送達される。種々の実施形態において、ベクターは、本明細書に企図される1つ以上のポリヌクレオチド配列を含む。用語「ベクター」は、別の核酸分子を転写または輸送することができる核酸分子を指すために本明細書で使用される。転写されたポリヌクレオチドは、一般に、例えば、ベクター核酸分子に連結、例えば、挿入される。ベクターは、細胞内の自律的複製を指示する配列を含んでもよく、または宿主細胞DNAへの組み込みを可能にするのに十分な配列を含んでもよい。ベクターは、生物、細胞、または細胞成分に標的ポリヌクレオチドを送達することができる。ある場合には、ベクターは発現ベクターである。本明細書で使用される「発現ベクター」は、そこに組み込まれるポリヌクレオチドの発現ならびに複製を促進することができるベクター、例えば、プラスミド、を指す。典型的には、発現される核酸配列は、シス作用調節配列、例えば、プロモーターおよび/またはエンハンサー配列に作動可能に連結され、プロモーターおよび/またはエンハンサーによる転写調節制御の対象となる。特定の場合、ベクターは、本開示の操作された受容体をコードする核酸分子を対象に送達するために使用される。
また、ベクターの薬学的調製物および結合剤の薬学的調製物を含む薬学的調製物も提供される。薬学的調製物は、操作された受容体をコードする主題のポリヌクレオチド(RNAまたはDNA)、主題の操作された受容体をコードするポリヌクレオチド(RNAまたはDNA)を有するベクター、または薬学的に許容されるビヒクル中に存在する結合剤を含む。「薬学的に許容されるビヒクル」は、ヒトなどの哺乳動物に使用するために、連邦政府または州政府の規制当局によって承認されているか、または米国薬局方もしくは他の一般に認められた薬局方に列挙されているビヒクルであり得る。用語「ビヒクル」は、本開示の化合物が哺乳動物への投与のために製剤化される際の希釈剤、アジュバント、賦形剤、または担体を指す。かかる薬学的ビヒクルは、ピーナッツ油、大豆油、鉱物油、ゴマ油等の石油、動物、植物または合成起源のものを含む、水および油等の液体であり得る。薬学的ビヒクルは、生理食塩水、アカシアガム、ゼラチン、デンプンペースト、タルク、ケラチン、コロイドシリカ、尿素等であり得る。加えて、補助剤、安定剤、増粘剤、潤滑剤および着色剤を使用してもよい。哺乳動物に投与される場合、本開示の化合物および組成物ならびに薬学的に許容されるビヒクル、賦形剤、または希釈剤は滅菌され得る。いくつかの場合において、本開示の化合物が静脈内投与されるとき、水、生理食塩水溶液、ならびにデキストロースおよびグリセロール水溶液等の水性培地がビヒクルとして用いられる。
本明細書に開示される組成物および方法を利用して、神経疾患または障害を治療することができる。本開示のいくつかの態様において、対象における神経疾患または障害を治療する方法が提供され、この方法は、操作された受容体をニューロン細胞に導入し、操作された受容体を活性化して細胞の活性を制御するリガンドを有効量で提供し、それによって対象における疼痛を軽減することを含む。いくつかの態様において、本明細書に開示されるベクターまたは組成物は、神経疾患または障害を治療するための医薬品の製造に使用される。
無知覚性疼痛症、灼熱痛(causlagia)、坐骨神経痛障害、変性関節障害、線維筋痛、内臓疾患、慢性疼痛障害、偏頭痛/頭痛、慢性疲労症候群、複合性局所疼痛症候群、神経ジストロフィー、足底筋膜炎または癌に関連する疼痛が挙げられる。
α7−nAChRからのリガンド結合ドメインおよびヒトGlyR1αからの塩化物導入イオン孔ドメインを含むキメラLGIC受容体を操作し、アセチルコリン、ニコチン、およびいくつかの低分子アゴニストリガンドに対する応答性について評価した。その後、これらの「親」キメラ受容体中にアミノ酸置換を生成し、これらのリガンドに対する応答性について変異体を再試験した。
受容体構築:個々の親キメラ受容体を、標準的な分子生物学的技術によって、BamHI部位およびEcoRI部位を使用してpcDNA3.1(+)(Invitrogen)にクローニングした。部位特異的変異誘発によってアミノ酸置換が導入された。
ヒト「α7−nAChR」の非天然小分子アゴニストへの曝露後に陰イオン電流を伝導するLGICを生成するために、α7−nAChRのリガンド結合ドメインに融合したヒトGlyR α1サブユニットの塩化物導入イオン孔ドメインを含む融合タンパク質を操作した。いくつかの融合タンパク質では、α7−nAChRのβ1−β2ループ配列および/またはCysループ配列を、GlyR α1からの対応する配列に置き換えた(図4の概略図を参照されたい)。他の融合タンパク質において、細胞外ドメインの3’配列とイオン孔ドメインの5’配列との間のジャンクション部位(「プレM1リンカー」)はシフトした。さらに他の融合タンパク質において、GlyR α1イオン孔ドメインの膜貫通ドメイン2と膜貫通ドメイン3との間の細胞外ループ配列(「M1−M2リンカー」)を、α7−nAChRからの対応するM1−M3リンカー配列に置き換えた。これらの操作されたキメラLGICの、天然リガンドであるアセチルコリンの用量範囲に対する応答を、アセチルコリンを1秒間適用した後の電気生理学によって評価した。各チャネルについて異なるEC50、Imax値、および脱感作動態が観察され(図3)、これらは、キメラのイオン孔ドメインに寄与するタンパク質の細胞外領域に対応するチャネル異種配列のリガンド結合ドメインに含めることが、イオンチャネルの特性を変化させることを示唆した。
α7−nAChRからのリガンド結合ドメインおよびヒトGlyR α1サブユニットからの塩化物導入イオン孔ドメインを含むキメラLGIC受容体は、小分子リガンドの投与後の神経障害性疼痛のラットモデルにおいて鎮痛を提供するそれらの有効性について評価される。
AAVベクター産生:8つの発現カセットは、標準的な分子生物学的技法を使用して構築される。いずれも、α7−nAChRのリガンド結合ドメインならびにGlyR α1のCysループドメインおよびイオン孔ドメインを含む操作されたキメラ受容体に連結したヒトシナプシン−1(hSYN)プロモーターを含有する。それらのデザインは以下の通りである:
(a)キメラ1:追加変更なし。
(b)キメラ2:1と同様であるが、図8Hからのアミノ酸置換も含み、このアミノ酸置換は、操作された受容体を、野生型受容体またはそれが由来する親キメラ受容体のいずれかよりもアセチルコリンに対する応答性を低くするが、非天然リガンドAZD−0328に対する受容体の応答性を維持する。
(c)キメラ3:1と同様であるが、図8A〜Fからのアミノ酸置換も含み、このアミノ酸置換は、操作された受容体を、野生型受容体またはそれが由来する親キメラ受容体のいずれかよりもアセチルコリンおよび非天然リガンドの両方に対する応答を低くする。
(d)キメラ4:同様であるが、図8Iからのアミノ酸置換を含み、このアミノ酸置換は、非天然リガンドAZD−0328およびファシニクリンのEC50を野生型受容体レベル程度に回復させる。
(e)キメラ5:1と同じであるが、GlyR α1からのβ1−2ループドメインも含む。
(f)キメラ6:2と同じであるが、GlyR α1からのβ1−2ループドメインも含む。
(g)キメラ7:3と同じであるが、GlyR α1由来のβ1−2ループドメインも含む。
(h)キメラ8:4と同じであるが、GlyR α1からのβ1−2ループドメインも含む。
このSNIモデルは、ラットの総腓骨神経と腓腹神経を切断し、脛骨分枝を隔離することによって作製される。ChaplanおよびYakshのアップダウン法を用いて、AAV.hSYN−α7−nAChR/GlyRα1を脊髄、DRG、または髄腔内空間に注入する前に機械的閾値を決定する。一方的ベクター注射の3週間後、動物を再び試験して、それらの機械的離脱閾値が変化しないことを検証する。最高回転数33rpmの加速ロータロッド(Stoelting、USA)を使用して、運動協調性も注入の前後に試験する。ラットがロータロッドに費やす持続時間が記録され、カットオフは300秒とした。各ラットは3つの訓練試験を経て、2時間後に検査を受ける。キメラ1およびキメラ5を受けた動物は、合成リガンドの不在下でさえ、多少の鎮痛を経験するようであり、これは、天然に存在するレベルのアセチルコリンがキメラ受容体を活性化している可能性があることを示唆している。試験中の残りの動物は、AAVの注入に起因する機械的離脱または運動協調性において変化を示さない。
非限定的な例では、慢性根性性疼痛を患っている患者は、本明細書に開示される組成物および方法を使用して治療される。患者は、1日目に、1つ以上の背根神経節に直接送達される(すなわち、腰部、頚部、または胸部DRGへの神経節内対流増強送達)、1.0mLの容積のAAV.hSYN−α7−nAChR/GlyRα1の1013ベクターゲノムで治療される。この実施例では、AAVベクターは、選択的ニューロン発現のためのヒトシナプシン−1(SYN1)プロモーターの制御下でα7−nAChR/GlyRα1キメラをコードする。注射の2週間後に、患者はAZD−0328の処方のために診療所に戻る。患者は、必要に応じて(すなわち、疼痛エピソード中)、0.1mg/kgのAZD−0328を経口的に自己投与する。
非限定的な例では、慢性頭蓋顔面痛(例えば、三叉神経痛または側頭下顎関節機能障害)を患っている患者は、本明細書に開示される組成物および方法を使用して治療される。患者は、1日目に、三叉神経節に直接送達される(すなわち、神経節内対流増強送達)、0.150mLの容積のAAV.hSYN−α7−nAChR/GlyRα1の1013ベクターゲノムで治療される。この実施例では、AAVベクターは、選択的ニューロン発現のためのヒトシナプシン−1(SYN1)プロモーターの制御下でα7−nAChR/GlyRα1キメラをコードする。注射の2週間後に、患者はAZD−0328の処方のために診療所に戻る。患者は、必要に応じて(すなわち、疼痛エピソード中)、0.1mg/kgのAZD−0328を経口的に自己投与する。
非限定的な例では、肥満を患っている患者は、本明細書に開示される組成物および方法を使用して治療される。患者は、1日目に、1013のAAVベクターゲノムで治療される。迷走神経の胃岐(すなわち、神経内)に直接送達される1.0mLの容積のグレリン−α7−nAChR/GlyRα1。この実施例では、AAVベクターは、選択的ニューロン発現のためのヒトグレリンプロモーターの制御下で操作された受容体をコードする。注射の2週間後に、患者はAZD−0328の処方のために診療所に戻る。患者は、過剰な体重減少のため(すなわち、食欲抑制のため)に、0.1mg/kgのAZD−0328を毎日経口的に自己投与する。
非限定的な例では、肥満を患っている患者は、本明細書に開示される組成物および方法を使用して治療される。患者は、1日目に、膵臓を神経支配する背根神経節に直接送達される(すなわち、神経節内)、1.0mLの容積のAAV−TRPV1−α7−nAChR/GlyRα1の1013ベクターゲノムで治療される。この実施例では、AAVベクターは、選択的ニューロン発現のためのヒトTRPV1プロモーターの制御下で操作された受容体をコードする。注射の2週間後に、患者はAZD−0328の処方のために診療所に戻る。患者は、過剰な体重減少のために0.1mg/kgのAZD−0328を毎日経口的に自己投与する。
非限定的な例では、肥満を患っている患者は、本明細書に開示される組成物および方法を使用して治療される。患者は、1日目に、視床下部の室傍核(PVH)に直接送達される(すなわち、頭蓋内対流増強送達)、1.0mLの容積のAAV−SIM1−α7−nAChR/GlyRα1の1013ベクターゲノムで治療される。この実施例では、AAVベクターは、プロオピオメラノコルチン(POMC)ニューロンにおける選択的ニューロン発現および最終的な食欲抑制経路の刺激のためのヒトシングルマインドファミリーBHLH転写因子1(SIM1)プロモーターの制御下で操作されたチャネルをコードする。注射の2週間後に、患者はAZD−0328の処方のために診療所に戻る。患者は、過剰な体重減少のため(すなわち、食欲抑制のため)に、0.15mg/kgのAZD−0328を毎日経口的に自己投与する。
非限定的な例では、外傷後ストレス障害(PTSD)を患っている患者は、本明細書に開示される組成物および方法を使用して治療される。患者は、1日目に、C6星状神経節に直接送達される(すなわち、神経節内)、1.0mLの容積のAAV−hSYN1−α7−nAChR/GlyRα1の1013ベクターゲノムで治療される。この実施例では、AAVベクターは、選択的ニューロン発現のためのヒトシナプシン−1(hSYN1)プロモーターの制御下で操作された受容体をコードする。注射の2週間後に、患者はAZD−0328の処方のために診療所に戻る。患者は、PTSD症状(すなわち、不安)のために0.15mg/kgのAZD−0328を毎日経口的に自己投与する。
非限定的な例では、治療抵抗性うつ病(TRD)を患っている患者は、本明細書に開示される組成物および方法を使用して治療される。患者は、1日目に、迷走神経に直接送達される(すなわち、神経内)、1.0mLの容積のAAV−hSYN1−α7−nAChR/GlyRα1の1013ベクターゲノムで治療される。この実施例では、AAVベクターは、選択的ニューロン発現のためのヒトシナプシン−1(hSYN1)プロモーターの制御下で操作された受容体をコードする。注射の2週間後に、患者はAZD−0328の処方のために診療所に戻る。患者は、うつ病症状に対して0.1mg/kgのAZD−0328を毎日経口的に自己投与する。
非限定的な例では、胃食道逆流症(GERD)を患っている患者は、本明細書に開示される組成物および方法を使用して治療される。患者は、1日目に、それぞれ下部食道括約筋(LES)迷走神経および腸筋層間神経叢(すなわち、神経内)または平滑筋(筋肉内)に直接送達される1.0mLの容積のAAV−hSYN1−α7−nAChR/GlyRα1またはAAV−CAG−α7−nAChR/GlyRα1の1013ベクターゲノムで治療される。この実施例では、AAVベクターは、選択的ニューロン発現のためのヒトシナプシン−1(hSYN1)プロモーターまたはLES筋細胞における発現のためのCAGプロモーターの制御下で操作された受容体をコードする。注射の2週間後に、患者はAZD−0328の処方のために診療所に戻る。患者は、GERDの症状(すなわち、酸逆流)に対して、0.15mg/kgのAD−0328を毎日経口的に自己投与する。
非限定的な例では、てんかんに関連する発作を患っている患者は、本明細書に開示される組成物および方法を使用して治療される。患者は、1日目に、運動皮質などの所定の発作焦点に直接送達される(すなわち、頭蓋内)、1.0mLの容積のAAV−CamKIIα−α7−nAChR/GlyRα1の1013ベクターゲノムで治療される。この実施例では、AAVベクターは、興奮性ニューロンにおける選択的ニューロン発現のためのヒトカルシウム/カルモジュリン依存性タンパク質キナーゼIIα(CamKIIα)プロモーターの制御下で操作された受容体をコードする。注射の2週間後に、患者はAZD−0328の処方のために診療所に戻る。患者は、てんかん症状(すなわち、発作)に対して、0.1mg/kgのAZD−0328を毎日経口的に自己投与する。
非限定的な例では、運動障害(例えば、パーキンソン病の振戦)を患っている患者は、本明細書に開示される組成物および方法を使用して治療される。患者は、1日目に、視床下核(すなわち、頭蓋内STN)に直接送達される、1.0mLの容積のAAV−CamKIIα−α7−nAChR/GlyRα1の1013ベクターゲノムで治療される。この実施例では、AAVベクターは、興奮性ニューロンにおける選択的ニューロン発現のためのヒトカルシウム/カルモジュリン依存性タンパク質キナーゼIIα(CamKIIα)プロモーターの制御下で操作された受容体をコードする。注射の2週間後に、患者はAZD−0328の処方のために診療所に戻る。患者は、運動障害の症状(すなわち、振戦)に対して、0.1mg/kgのAZD−0328を毎日経口的に自己投与する。
Claims (34)
- 操作された受容体であって、前記操作された受容体が、キメラリガンド依存性イオンチャネル(LGIC)受容体であり、
(a)第1の野生型CysループLGIC受容体に由来するリガンド結合ドメインと、
(b)第2の野生型CysループLGIC受容体からのCysループドメインと、
(c)前記第2の野生型CysループLGIC受容体に由来するイオン孔ドメインと、を含む、操作された受容体。 - 前記受容体が、前記第2の野生型CysループLGIC受容体からのβ1−2ループドメインをさらに含む、請求項1に記載の操作された受容体。
- 前記第1および前記第2の野生型CysループLGIC受容体が異なる、請求項1または2に記載の操作された受容体。
- 前記第1の野生型CysループLGIC受容体が、ヒトα7ニコチン性アセチルコリン受容体(α7−nAChR、配列番号4)である、請求項1〜3のいずれか一項に記載の操作された受容体。
- 前記第2の野生型CysループLGIC受容体が、ヒトグリシン受容体α1サブユニット(GlyRα1、配列番号2)である、請求項3または4に記載の操作された受容体。
- 前記Cysループドメインが、配列番号2のアミノ酸166〜180を含む、請求項5に記載の操作された受容体。
- 前記Cysループドメインが、配列番号2のアミノ酸166〜172を含む、請求項5に記載の操作された受容体。
- 前記β1−2ループドメインが、配列番号2のアミノ酸81〜84を含む、請求項5に記載の操作された受容体。
- 前記リガンド結合ドメインが、W77、Y94、R101、W108、Y115、T128、N129、V130、L131、Q139、L141、Y151、S170、W171、S172、S188、Y190、Y210、C212、C213、およびY217からなる群から選択されるα7−nAChRの残基に対応する残基の1つ以上のアミノ酸置換を含む、請求項1〜8のいずれか一項に記載の操作された受容体。
- 前記1つ以上のアミノ酸置換が、前記受容体上の非天然リガンドの効力を実質的に維持しながら、前記受容体上のアセチルコリンの効力を低下させる、機能喪失変異である、請求項9に記載の操作された受容体。
- 前記置換が、α7−nAChRのL131S、L131T、L131D、またはS172Dに対応する置換から選択される、請求項10に記載の操作された受容体。
- 前記非天然リガンドが、AZD−0328、TC6987、ABT−126、およびファシニクリン/RG3487から選択される、請求項10に記載の操作された受容体。
- 前記1つ以上のアミノ酸置換が、前記受容体上のアセチルコリンの効力を増加させる、機能獲得変異である、請求項9に記載の操作された受容体。
- 前記置換が、α7−nAChRのL131N、L141W、S170G、S170A、S170L、S170I、S170V、S170P、S170F、S170M、S170T、S170C、S172T、S172C、S188I、S188V、S188F、S188M、S188Q、S188T、S188P、またはS188Wに対応する置換から選択される、請求項13に記載の操作された受容体。
- 請求項1〜14のいずれか一項に記載の操作された受容体をコードするポリヌクレオチド。
- 請求項15に記載のポリヌクレオチドを含むベクター。
- 前記ベクターが、アデノウイルスベクター、レトロウイルスベクター、アデノ随伴ウイルス(AAV)ベクター、および単純ヘルペス1型ウイルスベクター(HSV−1)からなる群から選択されるウイルスベクターである、請求項16に記載のベクター。
- 前記AAVベクターが、AAV5もしくはそのバリアント、AAV6もしくはそのバリアント、またはAAV9もしくはそのバリアントである、請求項17に記載のウイルスベクター。
- 請求項15に記載のポリヌクレオチド、または請求項16〜18のいずれか一項に記載のベクターと、薬学的に許容されるビヒクルとを含む、薬学的組成物。
- 神経障害を改善する必要がある対象において神経障害を改善する方法であって、
請求項1〜15のいずれか一項に記載の操作されたリガンド依存性イオンチャネル(LGIC)受容体をコードするポリヌクレオチドを前記対象に投与することと、
前記対象に、前記操作されたLGIC受容体のアゴニストとして作用する結合剤を投与することと、を含む、方法。 - 前記ポリヌクレオチドが、非ウイルス法によって前記対象に投与される、請求項20に記載の方法。
- 前記非ウイルス法が、リポフェクション、ナノ粒子送達、微粒子銃、エレクトロポレーション、超音波処理、またはマイクロインジェクションである、請求項21に記載の方法。
- 前記ポリヌクレオチドが、ウイルスベクターにて前記対象に送達される、請求項20に記載の方法。
- 前記ウイルスベクターが、アデノウイルスベクター、レトロウイルスベクター、アデノ随伴ウイルス(AAV)ベクター、または単純ヘルペス1型ウイルスベクター(HSV−1)である、請求項23に記載の方法。
- 前記AAVベクターが、AAV5もしくはそのバリアント、AAV6もしくはそのバリアント、またはAAV9もしくはそのバリアントである、請求項24に記載の方法。
- 前記操作された受容体が、興奮性細胞において活性なプロモーターに作動可能に連結されている、請求項20〜25のいずれか一項に記載の方法。
- 前記興奮性細胞が、ニューロンまたは筋細胞である、請求項26に記載の方法。
- 前記ニューロンが、背根神経節、運動ニューロン、興奮性ニューロン、抑制性ニューロン、または感覚ニューロンである、請求項27に記載の方法。
- 前記対象が、疼痛、発作性障害、運動障害、摂食障害、脊髄損傷、神経因性膀胱、痙攣性障害、または掻痒を患っている、請求項20〜28のいずれか一項に記載の方法。
- 前記対象が、アルツハイマー病、パーキンソン病、外傷後ストレス障害(PTSD)、胃食道逆流症(GERD)、中毒、不安感、うつ病、記憶喪失、認知症、睡眠時無呼吸、脳卒中、ナルコレプシー、尿失禁、本態性振戦、運動障害、または心房細動を患っている、請求項20〜28のいずれか一項に記載の方法。
- 前記結合剤が、AZD0328、ABT−126、TC6987、またはファシニクリン/RG3487からなる群から選択される、請求項20〜30のいずれか一項に記載の方法。
- 前記ポリヌクレオチドが、皮下、経口、髄腔内、局所、静脈内、神経節内、神経内、頭蓋内、脊髄内、または大槽内に投与される、請求項20〜31のいずれか一項に記載の方法。
- 前記結合剤が、経口、皮下、局所、または静脈内に投与される、請求項20〜31のいずれか一項に記載の方法。
- 前記対象がヒトである、請求項20〜33のいずれか一項に記載の方法。
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US20230102192A1 (en) * | 2020-02-20 | 2023-03-30 | The Regents Of The University Of California | Therapies for the treatment of diseases and disorders associated with abnormal expression of a neural-associated gene |
BR112023003167A2 (pt) * | 2020-08-21 | 2023-05-02 | Trames Bio Inc | Composições e métodos para doenças neurológicas |
US20230381125A1 (en) * | 2020-09-25 | 2023-11-30 | The Regents Of The University Of California | Compositions and methods for ameliorating medical conditions |
CA3205877A1 (en) * | 2021-01-25 | 2022-07-28 | Annahita KERAVALA | Adeno-associated virus capsids and engineered ligand-gated ion channels for treating focal epilepsy and neuropathic pain |
WO2023278295A1 (en) | 2021-06-29 | 2023-01-05 | The Broad Institute, Inc. | Compositions and methods for ameliorating anterodorsal thalamus hyperexcitability |
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