JP2021527711A - 神経系疾患および障害の改善のための方法 - Google Patents
神経系疾患および障害の改善のための方法 Download PDFInfo
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Abstract
【選択図】なし
Description
本出願は、2018年6月14日に出願された米国仮特許出願第62/685,246号、同第62/685,247号および同第62/685,249号、2018年6月18日に出願された米国仮特許出願第62/686,658号、同第62/686,660号、および同第62/686,663号、2019年3月28日に出願された米国仮特許出願第62/825,571号、同第62/825,670号、同第62/825,675号、および同第62/825,702号の利益を主張するものである。前述の内容全体は、参照により本明細書に組み込まれる。
本開示の様々な態様および実施形態は、患者の認知の改善および/または神経変性疾患の治療のための組成物および方法に関する。
米国特許出願公開第2013/0096126号(特許文献1)には、「神経変性障害による学習、記憶、またはその両方の障害を有する哺乳類において、学習または記憶、その両方を増強する方法であって、β1アドレナリン受容体アゴニスト、部分的アゴニストまたは受容体リガンドである少なくとも1つの化合物またはその塩を、前述の哺乳類の学習、記憶、またはその両方を改善するのに有効な量で投与する工程を伴う方法」が開示されている。
一態様では、患者の認知機能の改善および/または神経変性疾患の治療方法が提供され、本方法は、認知機能の改善および/または神経変性疾患の治療を必要としているまたは望んでいる患者を特定する段階と、β1−ADRアゴニストを前述の患者に投与する段階と、を含む。
本開示のある特定の態様および実施形態では、組成物および方法は、患者の認知の改善、脳代謝活性の上昇、および/または炎症制御の改善をもたらす。いくつかの実施形態では、本明細書に記載の方法は、例えば、患者の記憶試験、精神状態、脳機能、精神条件の診断指標、文脈学習試験などの認知試験またはモデルにおいての改善によって実証されるように、認知の改善をもたらす。前述の認知試験、診断およびモデルは、当技術分野で周知である。様々な態様および実施形態では、動物もしくはヒトのための多くの許容される文脈学習試験のいずれかを使用して、ベースライン認知機能を評価する、および/または改善された認知機能を測定もしくは定量化することができる。いくつかの実施形態では、本明細書に記載の組成物および方法は、以下の1つ以上の試験、診断およびモデルの改善をもたらし得る。同様に、上昇した脳代謝活性および改善された炎症制御について、ある特定の実施形態では、これらは、FDG−PETを介して、および脳脊髄液(CSF)のサンプリングを介して画像化されることがあり、炎症性サイトカインおよびグリア細胞活性化のマーカーの測定を可能にする。MRI−ASLおよび/またはMRI−BOLDはまた、FDG−PETの有無にかかわらず利用することができる。
いくつかの実施形態では、動物モデルに適合した脳画像診断は、認知機能を監視するため、および/または本明細書に記載のような治療の有効性を評価するために使用してよい。いくつかの実施形態では、フルオロデオキシグルコース陽電子放出断層撮影(FDG−PET)は、例えば、Mirbolooki et al.,Synapse,(2015)69:96−98、およびCatus et al.,British Journal of Pharmacology,(2011)162:1700−1715に記載の神経画像処理に使用してもよい。Brown et al.,RadioGraphics,(2014)34:684−701、およびShivamurthy et al.,AJR,(2015)204:W76−W85も参照されたい。
様々な実施形態では、ベースライン認知機能を評価するため、および/またはヒト対象において改善された認知機能を測定もしくは定量化するために、本明細書に開示される組成物および方法とともに使用してよい、当技術分野では認識および/または許容されている文脈学習試験が多くある。例えば、使用される文脈学習試験は、シングルタスク学習、マルチタスク学習、または空間的文脈記憶に基づいてもよい。空間的文脈記憶に基づく文脈学習試験評価は、例えば、個人がショッピングモール、近隣、または市内交通機関もしくは地下鉄システムをどの程度良好に案内できるかを評価する際に、ならびに本明細書に記載の治療方法から生じるこれらのタスクを実行する能力の任意の改善を評価する際に有利であり得る。
AD脳病理は、近接脳の領域に病変を引き起こす高分解耐性アミロイド線維の蓄積を指す。神経毒性レベルにこれらのアミロイド線維が蓄積することにより、神経線維が破壊され、さらにアルツハイマー型認知症に関連した行動が観察されるようになる。疾患の進行とともに段階的に重症化する観察された行動症状には、語彙の喪失、誤った単語置換(錯語症)、読み書きスキルの喪失、転倒、徘徊、言葉の喪失、無気力、さらには筋肉量の喪失のリスクの増加が含まれることが多い。
数種のトリソミーマウスモデルの作製によって、DSにおける認知機能障害の神経生物学的根拠の解明が大いに容易になった。マウスモデルの中で、Ts65Dnマウスが最も特徴的である。これは、ヒト21番染色体(HSA21)上の遺伝子とオーソロガスである、16番染色体上の約140マウス遺伝子の追加コピーを有する。神経系異常に潜在的な役割を有するHSA21のほぼすべての遺伝子は、Ts65Dnマウスにも見出される。DSと同様に、Ts65Dnマウスにおいて、海馬の構造および機能の変化、ならびに長期増強(LTP)が誘導されないことが広く報告されている。Ts65Dnマウスは、DS研究において最も広く使用され、ヒトのDSに関する調査のための当技術分野で許容されるモデルであると考えられる。Olson,L.E.,et al.,Dev.Dyn.2004 July;230(3):581−9。
「薬学的に許容される塩」という用語は、ヒトまたは獣医学で一般的に使用され、使用上安全であると判断される酸付加塩を意味する。本開示の例として、例えば、酢酸、アスコルビン酸、ベンゼンスルホン酸、安息香酸、カンホスルホン酸、クエン酸、エタンスルホン酸、エジシル酸、フマル酸、ゲンチジン酸、グルコン酸、グルクロン酸、グルタミン酸、ヒプリル酸、臭化水素酸、イセチオン酸、乳酸、硝酸、リン酸、コハク酸、硫酸、および酒石酸から得られる塩が挙げられるが、これらに限定されない。そのような塩のいかなる水和物も、この定義に含まれる。したがって、例えば、フマル酸塩およびヘミフマル酸塩は両方、それらの水和物とともに、具体的に企図される。例えば、フマル酸塩二水和物が具体的に挙げられてもよい。
本実験では、9〜12ヶ月齢の、雄および雌のTs65Dnマウス(B6EiC3Sn−al A−Ts(1716)65Dn)、ならびにそれらの、年齢が適合する正常体型(2N)の同腹仔を使用する。すべての動物の遺伝子型は、実験を開始する前に、リアルタイム定量PCRによって判定される。網膜変性1突然変異遺伝子(Rd1)はマウスのバックグラウンドで保因されており、この遺伝子は劣性であるため、Rd1に関してホモ接合性のマウスは試験に使用されない。すべての動物は、水と食べ物に自由にアクセスできる、温度および湿度が制御された環境で、12時間の暗/明周期で飼育される。すべての試験は明周期で行われる。動物は、治療群および対照群に分けられ、本明細書に記載の治療レジメンのうちの1つに供される。動物は、治療レジメンの投与前、および再度治療または対照レジメンの後に、本明細書に記載の認知試験のうちの1つ以上に供される。治療レジメンを受ける動物は、認知試験の改善を示すが、対照動物は改善を示さない。
患者は、MCI、aMCI、血管性認知症、混合型認知症、FTD(前頭側頭型認知症;ピック病)、HD(ハンチントン病)、レット症候群、PSP(進行性核上性麻痺)、CBD(大脳皮質基底核変性症)、SCA(脊髄小脳失調症)、MSA(多系統萎縮症)、SDS(シャイ・ドレーガー症候群)、オリーブ橋小脳萎縮症、TBI(外傷性脳損傷)、CTE(慢性外傷性脳症)、脳卒中、WKS(ウェルニッケ・コルサコフ症候群;アルコール性認知症およびチアミン欠乏症)、正常圧水頭症、過眠症/ナルコレプシー、ASD(自閉症スペクトラム障害)、FXS(脆弱X症候群)、TSC(結節性硬化症複合体)、プリオン関連疾患(CJDなど)、うつ病性障害、DLB(レビー小体型認知症)、PD(パーキンソン病)、PDD(パーキンソン病認知症)、またはADHD(注意欠陥多動性障害)のうちの1つ以上と診断されたものとして特定される。いくつかの実施形態では、ナドロールは、患者に投与され、続いて、経皮吸収パッチを使用して、β1アゴニストを鼻腔内投与され得る。いくつかの実施形態では、ナドロールが患者に投与され、続いて、経皮吸収パッチを使用して、β2アゴニストが鼻腔内投与され得る。いくつかの実施形態では、ナドロールが患者に投与され、続いて、経皮吸収パッチを使用して、プレナルテロールが投与され得る。いくつかの実施形態では、ナドロールはまた、患者に投与され、続いて、経皮吸収パッチを使用して、ツロブテロールが投与され得る。治療レジメンは1ヶ月継続される。患者は、治療レジメンの開始前と治療レジメンの開始から約4週間後に、本明細書に記載の認知試験およびPETスキャンを受ける。患者は、治療レジメン後に認知試験の改善を示し、PETスキャンは、脳疾患の指標に関して改善を示す。
一態様では、本発明は、患者の認知機能の改善および/または神経変性疾患の治療方法を提供する。方法は、認知機能の改善および/または神経変性疾患の治療を必要としているまたは望んでいる患者を特定する段階と、β1−ADRアゴニストおよび末梢作用型β遮断薬(PABRA)を前述の患者に投与する段階と、を含む。
Claims (27)
- 患者の認知機能の改善および/または神経変性疾患の治療の方法であって、
認知機能の改善および/または神経変性疾患の治療を必要としているまたは望んでいる患者を特定する段階と、
β1−ADRアゴニストおよび末梢作用型β遮断薬(PABRA)を前記患者に投与する段階と
を含む、方法。 - 前記β1−ADRアゴニストが、キサモテロールである、請求項1に記載の方法。
- 前記β1−ADRアゴニストが、ピンドロールである、請求項1に記載の方法。
- 患者の認知機能の改善および/または神経変性疾患の治療の方法であって、
認知機能の改善および/またはパーキンソン病、レビー小体型認知症、ダウン症候群、もしくはアルツハイマー病を有しない神経変性疾患の治療を必要としているまたは望んでいる患者を特定する段階と、
β2−ADRアゴニストおよび末梢作用型β遮断薬(PABRA)を前記患者に投与する段階と
を含む、方法。 - 患者の認知機能の改善および/または神経変性疾患の治療の方法であって、
認知機能の改善および/または神経変性疾患の治療を必要としているまたは望んでいる患者を特定する段階と、
前記患者の体重1kg当たり約0.1μg〜1.5gの用量のβ2−ADRアゴニストおよび末梢作用型β遮断薬(PABRA)を前記患者に投与する段階と
を含む、方法。 - 前記β2−ADRアゴニストが、前記患者の体重1kg当たり約1μg〜100mgの用量で投与される、請求項5に記載の方法。
- 患者の認知機能の改善および/または神経変性疾患の治療の方法であって、
認知機能の改善および/または神経変性疾患の治療を必要としているまたは望んでいる患者を特定する段階と、
プレナルテロールを前記患者に投与する段階と
を含む、方法。 - 患者の認知機能の改善および/または神経変性疾患の治療の方法であって、
認知機能の改善および/または神経変性疾患の治療を必要としているまたは望んでいる患者を特定する段階と、
プレナルテロールおよび末梢作用型β遮断薬(PABRA)を前記患者に投与する段階と
を含む、方法。 - 患者の認知機能の改善および/または神経変性疾患の治療の方法であって、
認知機能の改善および/または神経変性疾患の治療を必要としているまたは望んでいる患者を特定する段階と、
ツロブテロールを前記患者に投与する段階と
を含む、方法。 - 患者の認知機能の改善および/または神経変性疾患の治療の方法であって、
認知機能の改善および/または神経変性疾患の治療を必要としているまたは望んでいる患者を特定する段階と、
ツロブテロールおよび末梢作用型β遮断薬(PABRA)を前記患者に投与する段階と
を含む、方法。 - 前記プレナルテロールが、経皮吸収パッチで投与される、前記請求項のいずれか一項に記載の方法。
- 前記プレナルテロールが、ラセミ混合物として投与される、前記請求項のいずれか一項に記載の方法。
- 前記ツロブテロールが、経皮吸収パッチで投与される、前記請求項のいずれか一項に記載の方法。
- 前記ツロブテロールが、ラセミ混合物として投与される、前記請求項のいずれか一項に記載の方法。
- 前記プレナルテロールが、(R)−プレナルテロールを実質的に含まない(S)−プレナルテロールである、前記請求項のいずれか一項に記載の方法。
- 前記プレナルテロールが、(S)−プレナルテロールを実質的に含まない(R)−プレナルテロールである、前記請求項のいずれか一項に記載の方法。
- 前記ツロブテロールが、(R)−ツロブテロールを実質的に含まない(S)−ツロブテロールである、前記請求項のいずれか一項に記載の方法。
- 前記ツロブテロールが、(S)−ツロブテロールを実質的に含まない(R)−ツロブテロールである、前記請求項のいずれか一項に記載の方法。
- 前記プレナルテロールが鼻腔内投与され、前記末梢作用型β遮断薬(PABRA)が、存在する場合、末梢に投与される、前記請求項のいずれか一項に記載の方法。
- 前記ツロブテロールが鼻腔内投与され、前記末梢作用型β遮断薬(PABRA)が、存在する場合、末梢に投与される、前記請求項のいずれか一項に記載の方法。
- 前記神経変性疾患が、MCI、aMCI、血管性認知症、混合型認知症、FTD(前頭側頭型認知症;ピック病)、HD(ハンチントン病)、レット症候群、PSP(進行性核上性麻痺)、CBD(大脳皮質基底核変性症)、SCA(脊髄小脳失調症)、MSA(多系統萎縮症)、SDS(シャイ・ドレーガー症候群)、オリーブ橋小脳萎縮症、TBI(外傷性脳損傷)、CTE(慢性外傷性脳症)、脳卒中、WKS(ウェルニッケ・コルサコフ症候群;アルコール性認知症およびチアミン欠乏症)、正常圧水頭症、過眠症/ナルコレプシー、ASD(自閉症スペクトラム障害)、FXS(脆弱X症候群)、TSC(結節性硬化症複合体)、プリオン関連疾患(CJDなど)、うつ病性障害、DLB(レビー小体型認知症)、PD(パーキンソン病)、PDD(パーキンソン病認知症)、ADHD(注意欠陥多動性障害)、およびダウン症候群からなる群から選択される1つ以上である、前記請求項のいずれか一項に記載の方法。
- 前記神経変性疾患が、MCI、aMCI、血管性認知症、混合型認知症、FTD(前頭側頭型認知症;ピック病)、HD(ハンチントン病)、レット症候群、PSP(進行性核上性麻痺)、CBD(大脳皮質基底核変性症)、SCA(脊髄小脳失調症)、MSA(多系統萎縮症)、SDS(シャイ・ドレーガー症候群)、オリーブ橋小脳萎縮症、TBI(外傷性脳損傷)、CTE(慢性外傷性脳症)、脳卒中、WKS(ウェルニッケ・コルサコフ症候群;アルコール性認知症およびチアミン欠乏症)、正常圧水頭症、過眠症/ナルコレプシー、ASD(自閉症スペクトラム障害)、FXS(脆弱X症候群)、TSC(結節性硬化症複合体)、プリオン関連疾患(CJDなど)、うつ病性障害、DLB(レビー小体型認知症)、PD(パーキンソン病)、PDD(パーキンソン病認知症)、およびADHD(注意欠陥多動性障害)からなる群から選択される1つ以上である、前記請求項のいずれか一項に記載の方法。
- 前記患者がアルツハイマー病を有しない、前記請求項のいずれか一項に記載の方法。
- 前記患者がダウン症候群を有しない、前記請求項のいずれか一項に記載の方法。
- 前記末梢作用型β遮断薬(PABRA)が、存在する場合、ナドロール、アテノロール、ソタロール、およびラベタロールからなる群から選択される1つ以上である、前記請求項のいずれか一項に記載の方法。
- 前記末梢作用型β遮断薬(PABRA)が、ナドロールである、前記請求項のいずれか一項に記載の方法。
- 前記末梢作用型β遮断薬(PABRA)が、アテノロールである、前記請求項のいずれか一項に記載の方法。
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US5281607B1 (en) * | 1992-10-08 | 1998-05-19 | Univ New York | Method of using alpha 2-antagonists for the treatment of neurodegenerative diseases |
US20130096126A1 (en) * | 2010-04-22 | 2013-04-18 | The Board Of Trustees Of The Leland Stanford Junior University | Method for enhancing learning and memory impaired by neurodegenerative disorders and compounds and compositions for effecting the same |
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