JP2020511473A - 発作性疾患の治療におけるデザイナー化合物によりのみ活性化するデザイナー受容体の使用 - Google Patents
発作性疾患の治療におけるデザイナー化合物によりのみ活性化するデザイナー受容体の使用 Download PDFInfo
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Abstract
Description
この出願は、2017年3月15日に出願の米国仮出願第62/471,635号、2017年12月20日に出願の第62/608,207号、および2018年2月27日に出願の第62/635,871号の利益および優先権を請求するものである(これらの全ては、出典明示によりそれら全体が本明細書に取り込まれる)。
本願は、デザイナー化合物によりのみ活性化するデザイナー受容体ならびに合成リガンドおよび超音波を用いる発作性疾患の治療に関する。
治療を必要とする患者における発作性疾患の治療方法であって、改変された受容体の標的部位への送達のための改変された受容体をコードするベクターを前記患者に投与することであって、前記改変された受容体は、合成リガンドにより活性化されるように改変されており、前記改変された受容体は、活性化されるとニューロン発火を阻害するものであり、次いで前記合成リガンドを前記患者に投与することを特徴とする方法が、提供される。実施態様において、前記受容体は、ヒトムスカリン性アセチルコリン受容体に由来する。実施態様において、前記受容体は、改変されたGタンパク質−共役受容体である。実施態様において、前記改変された受容体は、hM4Diである。実施態様において、前記改変された受容体は、KORDである。治療を必要とする患者における発作性疾患の治療方法であって、改変された受容体の標的部位への送達のための改変された受容体をコードするベクターを前記患者に投与することであって、前記改変された受容体は、合成リガンドにより活性化されるように改変されており、前記改変された受容体は、活性化されるとニューロン発火を増加させるものであり、次いで前記合成リガンドを前記患者に投与することを特徴とする方法が提供される。実施態様において、前記受容体は、ヒトムスカリン性アセチルコリン受容体に由来する。実施態様において、前記受容体は、改変されたGタンパク質−共役受容体である。実施態様において、前記改変された受容体は、hM3Dqである。
発作性疾患を治療するための方法および組成物であって、改変された受容体の標的部位への送達のための改変された受容体をコードするベクターを前記患者に投与することであって、前記改変された受容体は、合成リガンドにより活性化されるように改変されており、前記改変された受容体は、活性化されるとニューロン発火を阻害するものであり;次いで前記合成リガンドを前記患者に投与することを特徴とする方法および組成物が、本明細書において記載される。治療を必要とする患者における発作性疾患を治療するための方法および組成物であって、改変された受容体の標的部位への送達のための改変された受容体をコードするベクターを前記患者に投与することであって、前記改変された受容体は、合成リガンドにより活性化されるように改変されており、前記改変された受容体は、活性化されるとニューロン発火を増加させるものであり;次いで前記合成リガンドを前記患者に投与することを特徴とする方法および組成物もまた、本明細書に記載される。実施態様において、前記改変された受容体は、hM4Diである。実施態様において、hM4Diをコードするベクターは、発作性疾患に罹っている患者に投与される。実施態様において、前記改変された受容体は、hM3Dqである。実施態様において、hM3Dqをコードするベクターは、発作性疾患に罹っている患者に投与される。実施態様において、前記改変された受容体は、KORDである。実施態様において、KORDをコードするベクターは、発作性疾患に罹っている患者に投与される。実施態様において、発作性疾患を治療するための方法および組成物には、超音波を患者の脳における標的部位に適用して、標的部位における前記患者の血液脳関門の透過性を高めることが含まれる。
表I
ATC TAG GAA TTC ATG GCC AAC TTC ACA CCT GTC[配列番号:3]順向き
ATC TAG AAG CTT CTA CCT GGC AGT GCC GAT GTT CCG[配列番号:4]逆向き。
表II
本明細書で供される実施例は、本明細書に記載の開示を単に増強させるためのものであり、いずれに関して限定するものと考慮されるべきではない。
マウス発作モデルにおける化学遺伝学的治療の有効性の前向き評価
1日目に、50匹のマウスに、イソフルラン麻酔をかけて、海馬にカイニン酸(KA、200ng/nl)を注入する。21日目に、AAV2/7−CamKIIa−hM4Di−mCherry(4.66E+13ゲノムコピー/ml)を、硬化した海馬に注射する(500nl)。25日目に、IHKAコントロールマウスAAV2.7−CamKIIα−mCherryコントロールベクターを注射する。同時に、双極記録電極を海馬に埋め込む。42日目、海馬の発作波を頻発するマウス(15〜20発作/時間)をペルラピン効果の評価のために選択する。動物の約20%〜25%(5〜6匹のマウス/群)を試験する。EEGを連続して記録し、記録したシグナルをさらに処理して発作の回数を定量する。ペルラピンを0.1mg/kg、0.5mg/kg、1mg/kg、3mg/kg、5mg/kg、7mg/kgおよび10mg/kgの用量で投与する。注射は、各投薬間を少なくとも3日間で腹腔内に施す(約10日間)。マウスを評価して、副作用なく長期発作抑制を供する用量を決定する。終点は、発作抑制の少なくとも8時間である。最適な用量を決定したら、慢性投与は、1日1〜3回の投薬で少なくとも5日間について評価する。
マウス発作モデルにおける超音波で高めた化学遺伝学的治療の有効性の前向き評価
1日目に、50匹のマウスに、2%のイソフルラン麻酔にかけて、海馬にカイニン酸(KA、200ng/nl)を注入する。21日目に、AAV2/7−pAM/CaMKII−hM4D(Gi)−WPRE−BGHpA(4.66E+13ゲノムコピー/ml)を硬化した海馬に注射する(500nl)。25日目に、IHKAコントロールマウスAAV2/7−pAM/CaMKII−pL−WPRE−bGHpAコントロールベクターを注射する。42日目に、海馬の発作波を頻発するマウス(15〜20回の発作/時間)をペルラピンおよび超音波効果の評価のために選択する。動物の約20%〜25%(5〜6マウス/群)を試験する。EEGを連続して記録し、記録したシグナルをさらに処理して発作の回数を定量する。
マウス発作モデルにおける化学遺伝学的治療の有効性の前向き評価
1日目に、50匹のマウスに、イソフルラン麻酔にかけて、海馬にカイニン酸(KA,200ng/nl)を注入する。21日目に、AAVRec3−pAM/CaMKII−hM4D(Gi)−WPRE−BGHpA(4.66E+13ゲノムコピー/ml)を、硬化した海馬に注射する(500nl)。25IHKAコントロールマウスにおいて、AAVRec3−pAM/CaMKII−pL−WPRE−bGHpAコントロールベクターを注射する。同時に、双極記録電極を海馬に埋め込む。42日目に、海馬の発作波を頻発するマウス(15〜20発作/時間)をCNO効果の評価のために選択する。動物の約20%〜25%(5〜6匹マウス/群)を試験する。EEGを連続して記録し、記録したシグナルをさらに処理して発作の回数を定量する。CNOを0.1mg/kg、0.5mg/kg、1mg/kg、3mg/kg、5mg/kg、10mg/kgおよび15mg/kgの用量で投与する。注射は、各投薬間を少なくとも3日間で腹腔内に施す(約10日間)。マウスを評価して、副作用なく長期発作抑制を供する用量を決定する。終点は、発作抑制の少なくとも8時間である。最適な用量を決定したら、慢性投与は、1日1〜3回の投薬で少なくとも5日間について評価する。
マウス発作モデルにおける超音波で高まった化学遺伝学的治療の有効性の前向き評価
1日目に、50匹のマウスに、2%のイソフルラン麻酔にかけて、海馬にカイニン酸(KA,200ng/nl)を注入する。21日目に、AAVRec3−pAM/CaMKII−hM4D(Gi)−WPRE−BGHpA(4.66E+13ゲノムコピー/ml)を、硬化した海馬に注射する(500nl)。25IHKAコントロールマウスにおいて、AAVRec3−pAM/CaMKII−pL−WPRE−bGHpAコントロールベクターを注射する。42日目に、海馬の発作波を頻発するマウス(15〜20発作/時間)をCNおよび超音波効果の評価のために選択する。動物の約20%〜25%(5〜6匹マウス/群)を試験する。EEGを連続して記録し、記録したシグナルをさらに処理して発作の回数を定量する。
Claims (18)
- 治療を必要とする患者における発作性疾患の治療方法であって:
標的部位へのhM4Diの送達のためのhM4Diをコードするアデノ随伴ウイルスベクターを前記患者に投与することであって、前記ベクターは、ヒトCaMK2Aプロモーター、ウッドチャック肝炎ウイルスの転写後調節エレメント、およびウシ成長ホルモンポリアデニル化配列を含むものであり;次いで
hM4Diを活性化する合成リガンドを前記患者に投与すること
を特徴とする方法。 - 前記ベクターが、2つの逆位末端反復配列、SV40複製起点、pUC19複製起点、およびアンピシリン耐性遺伝子を含むものである、請求項1に記載の発作性疾患の治療方法。
- 前記ベクターが、pAM/hCaMK2A−hM4D(Gi)−WPRE−BGHpAである、請求項2に記載の発作性疾患の治療方法。
- 前記ベクターが、蛍光レポーター遺伝子を含むものである、請求項1に記載の発作性疾患の治療方法。
- 前記アデノ随伴ウイルスベクターが、AAV1、AAV2、AAV4、AAV5、AAV7、AAV8、またはAAV9である、請求項1に記載の発作性疾患の治療方法。
- 前記アデノ随伴ウイルスベクターが、AAVRec3である、請求項1に記載の発作性疾患の治療方法。
- 前記合成リガンドが、クロザピンN−オキシドである、請求項1に記載の発作性疾患の治療方法。
- 前記合成リガンドが、ペルラピンである、請求項1に記載の発作性疾患の治療方法。
- 前記ベクターが、患者の脳における標的部位に送達されるものである、請求項1に記載の発作性疾患の治療方法。
- 前記ベクターが、経口、頬側、舌下、経直腸、局所、鼻腔内、膣内、および非経口からなる群から選択される経路により投与されるものである、請求項1に記載の発作性疾患の治療方法。
- 前記ベクターが、患者の頭蓋を通して標的部位に直接投与されるものである、請求項9に記載の発作性疾患の治療方法。
- 前記合成リガンドが、経口、頬側、舌下、経直腸、局所、鼻腔内、膣内、および非経口からなる群から選択される経路により投与されるものである、請求項1に記載の発作性疾患の治療方法。
- 前記発作性疾患が、限局性皮質異形成、てんかん、全身性強直性間代性発作を伴うてんかん、ミオクロニー欠神てんかん、前頭葉てんかん、側頭葉てんかん、後頭葉てんかん、頭頂葉てんかん、ランドウ・クレフナー症候群、ラスムッセン症候群、ドラベ症候群、ドゥーゼ症候群、CDKL5障害、点頭てんかん(ウエスト症候群)、若年性ミオクローヌスてんかん(JME)、ワクチン関連脳症、難治性小児期てんかん(ICE)、レノックス・ガストー症候群(LGS)、レット症候群、大田原症候群、CDKL5障害、小児欠神てんかん、本態性振戦、急性頻回発作、良性ローランドてんかん、てんかん重積状態、難治性てんかん重積状態、超難治性てんかん重積状態(SRSE)、PCDH19小児てんかん、脳腫瘍誘発発作、過誤腫誘発発作、薬物離脱誘発発作、アルコール離脱誘発発作、増加した発作活動、および再発発作からなる群から選択されるものである、請求項1に記載の発作性疾患の治療方法。
- 前記発作性疾患が、焦点発作によって特徴付けられるものである、請求項1に記載の発作性疾患の治療方法。
- 前記方法が、運動失調、歩行障害、発話障害、発声、不随意的な笑い、認知障害、運動能力の異常、臨床的発作、潜在性発作、低血圧、筋緊張亢進、流涎、おしゃべり行動、前兆、痙攣、繰り返し行動、異常感覚、発作の頻度、および発作の重症度からなる群から選択される少なくとも1つの症状における改善を供するものである、請求項1に記載の発作性疾患の治療方法。
- ヒトCaMK2Aプロモーターの調節制御下のhM4Di、ウッドチャック転写後調節エレメント、およびウシ成長ホルモンポリアデニル化配列をコードする核酸を含む、ベクター。
- 2つの逆位末端反復配列、SV40複製起点、pUC19複製起点、およびアンピシリン耐性遺伝子をさらに含む、請求項16に記載のベクター。
- 前記ベクターが、pAM/hCaMK2A−hM4D(Gi)−WPRE−BGHpAである、請求項16に記載のベクター。
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CN111417397A (zh) * | 2017-12-06 | 2020-07-14 | 奥维德医疗公司 | Mir101或mir128在治疗发作性疾病中的用途 |
WO2019113538A2 (en) * | 2017-12-07 | 2019-06-13 | California Institute Of Technology | Methods and systems for noninvasive control of brain cells and related vectors and compositions |
WO2019126473A1 (en) * | 2017-12-20 | 2019-06-27 | Ovid Therapeutics Inc. | USE OF hM4Di IN THE TREATMENT OF SEIZURE DISORDERS |
WO2020106927A1 (en) | 2018-11-21 | 2020-05-28 | Certego Therapeutics | Gaboxadol for reducing risk of suicide and rapid relief of depression |
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US20160375097A1 (en) * | 2014-03-13 | 2016-12-29 | Ucl Business Plc | Combined use of a vector encoding a modified receptor and its exogenous agonist in the treatment of seizures |
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US20060292117A1 (en) * | 2002-04-17 | 2006-12-28 | Loiler Scott A | Improved rAAv vectors |
US20160375097A1 (en) * | 2014-03-13 | 2016-12-29 | Ucl Business Plc | Combined use of a vector encoding a modified receptor and its exogenous agonist in the treatment of seizures |
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IL269310A (en) | 2019-11-28 |
CA3056410A1 (en) | 2018-09-20 |
EP3595669A1 (en) | 2020-01-22 |
KR20190124309A (ko) | 2019-11-04 |
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