JP2021514010A - 運動障害を処置するための方法および組成物 - Google Patents
運動障害を処置するための方法および組成物 Download PDFInfo
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Abstract
Description
本出願は、2018年2月20日出願の米国仮出願第62/632,957号および2018年11月6日出願の米国仮出願第62/756,513号(これらは本明細書に参考として援用される)の利益を主張する。
骨格筋は、2つの主要な目的を果たす、人体で最大の器官系である。その第1は、筋収縮、自発運動、および姿勢維持を可能にする力の生成である;その第2は、グルコース、脂肪酸およびアミノ酸の代謝である。日々の活動およびエクササイズの間の骨格筋の収縮は、筋の適応に重要である、筋ストレス、破壊およびリモデリングへと自然につながっている。神経筋の病気(例えば、デュシェンヌ型筋ジストロフィー(DMD))を有する個体では、筋収縮は、身体が修復するのに苦労する、連続したラウンドの増幅された筋破壊をもたらす。最終的には、患者が加齢するにつれて、筋における過度の炎症、線維症、および脂肪沈着の蓄積をもたらす病態生理学的プロセスが出現し、身体機能の急激な低下および死亡率への寄与を予示する。
いくつかの局面において、神経筋の病気を処置する方法が、本明細書で記載される。上記方法は、その必要のある被験体に、骨格筋収縮のインヒビターを投与する工程を包含し得る。骨格筋収縮のインヒビターは、骨格筋収縮を、上記被験体の処置前の骨格筋収縮能力に対して90%低減するために必要とされる量より少ない量で投与され得る。
ある種の局面において、本開示は、速筋線維骨格筋ミオシンの選択的阻害を通じて神経筋の病気を処置するための方法を提供する。特に、本開示の方法は、DMDおよび他の神経筋の病気の処置において使用され得る。
Claims (37)
- 神経筋の病気を処置する方法であって、前記方法は、その必要のある被験体に、骨格筋収縮のインヒビターを投与する工程を包含し、ここで前記骨格筋収縮のインヒビターは、骨格筋収縮を、前記被験体の処置前の骨格筋収縮能力に対して90%低減するために必要な量より少ない量で投与される、方法。
- 神経筋の病気を処置する方法であって、前記方法は、その必要のある被験体に、骨格筋収縮のインヒビターを投与する工程を包含し、ここで前記骨格筋収縮のインヒビターは、骨格筋収縮を、前記被験体の処置前の骨格筋収縮能力に対して5%〜75%低減する量で投与される、方法。
- 神経筋の病気を処置する方法であって、前記方法は、その必要のある被験体に、骨格筋収縮のインヒビターを投与する工程を包含し、ここで前記骨格筋収縮のインヒビターは、クレアチニンキナーゼを、前記被験体の処置前のクレアチニンキナーゼレベルに対して5〜90%まで調節する量で投与される工程を包含する、方法。
- 神経筋の病気を処置する方法であって、前記方法は、その必要のある被験体に、骨格筋収縮のインヒビターを投与する工程を包含し、ここで前記骨格筋収縮のインヒビターは、炎症マーカーを、前記被験体の処置前の値に対して5〜90%まで調節する量で投与され、ここで前記炎症マーカーは、IL−1、IL−6およびTNF−α、または核磁気共鳴画像法を使用して測定され得る浮腫のような状態からなる群より選択される、方法。
- 神経筋の病気を処置する方法であって、前記方法は、その必要のある被験体に、骨格筋収縮のインヒビターを投与する工程を包含し、ここで前記骨格筋収縮のインヒビターは、骨格筋収縮を、エキソビボアッセイ:
a.mdxマウスから解剖した長趾伸筋を、電磁気プラーに据え付け、前記筋を、酸素化クレブス溶液中に浸して、筋機能を維持する;
b.試験化合物を、前記筋に適用する;
c.等尺性収縮工程を行い、ここで前記筋を、一連の6回の電気パルスで刺激する;
d.伸張性収縮工程を行い、ここで前記筋を、0.35〜0.7秒間にわたって80〜125Hzの一連の5〜6回の電気パルスで刺激し、前記刺激の最後の0.15〜0.2秒間の間にその静止長より10%〜20%大きく伸ばし、ここで各パルスの後に、筋収縮によって生じた筋力を測定する;
e.工程dにおける第1のパルスから第6のパルスまでの筋収縮によって生じた筋力の変化を、試験筋力の低下として計算し、前記試験化合物への曝露なしの対照のサンプルにおける第1のパルスから第6のパルスまでの筋収縮によって生じた筋力の変化(対照の筋力低下)と比較する;
において5%〜75%低減し、
ここで前記試験筋力の低下が、前記対照の筋力低下より少なくとも20%小さい場合に、前記試験化合物は、骨格筋収縮のインヒビターである、方法。 - 神経筋の病気を処置する方法であって、前記方法は、その必要のある被験体に、骨格筋収縮のインヒビターを投与する工程を包含し、ここで前記骨格筋収縮のインヒビターは、以下のアッセイ:
a.ミオシンS1フラグメントを、重合化アクチンとともに、対照の容器および試験容器中でインキュベートする;
b.試験化合物およびMgATPを前記試験容器中の混合物に添加し、MgATPを前記対照の容器に添加する;
c.前記対照の容器および試験容器を、前記対照の容器中のATPのうちの95%またはこれより多くが加水分解されるまでインキュベートする;
においてATPase活性を阻害し、
前記試験容器中のATP消費の量を、前記対照の容器中のATP消費の量と比較し、ここで前記試験容器中のATP消費が前記対照の容器より少なくとも20%小さい場合、前記試験化合物は、骨格筋収縮のインヒビターである、方法。 - 神経筋の病気を処置する方法であって、前記方法は、
a.被験体の心筋収縮または前記心筋収縮からの筋力を測定する工程;
b.その必要のある被験体に、骨格筋収縮のインヒビターを投与する工程:
c.前記骨格筋収縮のインヒビターの投与後に、前記被験体の前記心筋収縮または心筋収縮からの筋力を測定する工程;
を包含し、ここで前記工程aの心筋収縮は、前記工程cの心筋収縮の10%以内である、方法。 - 前記神経筋の病気は、デュシェンヌ型筋ジストロフィー、ベッカー型筋ジストロフィー、筋強直性ジストロフィー1型、筋強直性ジストロフィー2型、顔面肩甲上腕型筋ジストロフィー、眼咽頭型筋ジストロフィー、肢帯型筋ジストロフィー、腱炎、手根管症候群から選択される、請求項1〜7のいずれか1項に記載の方法。
- 前記骨格筋収縮のインヒビターは、ミオシンのインヒビターから選択される、請求項1〜7のいずれか1項に記載の方法。
- 前記ミオシンのインヒビターは、骨格筋ミオシンIIのインヒビターである、請求項9に記載の方法。
- 運動障害を処置する方法であって、前記方法は、その必要のある被験体に、骨格筋ミオシンIIのインヒビターを投与する工程を包含する方法。
- 前記運動障害は、筋痙縮を含む、請求項11に記載の方法。
- 前記筋痙縮は、多発性硬化症、パーキンソン病、アルツハイマー病、もしくは脳性麻痺、または傷害、または脳卒中、外傷性脳損傷、脊髄損傷、低酸素症、髄膜炎、脳炎、フェニルケトン尿症、もしくは筋萎縮性側索硬化症のような外傷性事象と関連する痙縮から選択される、請求項12に記載の方法。
- 前記骨格筋ミオシンIIのインヒビターは、不随意的筋収縮を90%低減するために十分な量で投与される、請求項11に記載の方法。
- 前記骨格筋ミオシンIIのインヒビターは、不随意的筋収縮を25〜75%低減するために十分な量で投与される、請求項11に記載の方法。
- 前記骨格筋ミオシンIIのインヒビターは、日常生活動作(ADL)または習慣的身体活動に影響しない、請求項11〜15のいずれか1項に記載の方法。
- 前記骨格筋収縮のインヒビターは、日常生活動作(ADL)または習慣的身体活動に影響しない、請求項1〜10のいずれか1項に記載の方法。
- 前記方法は、前記骨格筋ミオシンIIインヒビターを前記被験体に投与する前および投与した後に、前記被験体の骨格筋収縮または前記骨格筋収縮からの筋力を測定する工程をさらに包含する、請求項1〜10のいずれか1項に記載の方法。
- 前記投与の前の前記被験体の骨格筋収縮は、前記被験体への前記投与の後の骨格筋収縮の20%以内である、請求項17に記載の方法。
- 前記投与の前の前記被験体の骨格筋収縮は、前記被験体への前記投与の後の筋収縮の10%以内である、請求項17に記載の方法。
- 前記骨格筋ミオシンIIのインヒビターは、前記被験体の心筋収縮または前記心筋収縮からの筋力を感知できるほど阻害しない、請求項11〜16のいずれか1項に記載の方法。
- 前記骨格筋ミオシンIIのインヒビターは、前記被験体の肺における1回換気量を感知できるほど阻害しない、請求項11〜16のいずれか1項に記載の方法。
- 前記方法は、前記骨格筋ミオシンIIインヒビターの投与前および投与後に、前記被験体の心筋収縮または前記心筋収縮からの筋力を測定する工程をさらに包含する、請求項11〜16のいずれか1項に記載の方法。
- 前記投与の前の前記被験体の心筋収縮は、前記被験体への前記投与の後の心筋収縮の10%以内である、請求項23に記載の方法。
- 骨格筋線維における収縮誘導性損傷は、不随意的骨格筋収縮に由来する、請求項24に記載の方法。
- 前記不随意的骨格筋収縮は、神経筋の病気または痙縮に関連する病気と関連する、請求項25に記載の方法。
- 前記神経筋の病気は、デュシェンヌ型筋ジストロフィーである、請求項26に記載の方法。
- 骨格筋線維における収縮誘導性損傷は、随意的骨格筋収縮に由来する、請求項23に記載の方法。
- 前記方法は、前記骨格筋ミオシンIIインヒビターを投与する前および投与した後に、前記被験体の心筋収縮または前記心筋収縮からの筋力を測定する工程をさらに包含する、請求項23〜28のいずれか1項に記載の方法。
- 前記骨格筋ミオシンIIのインヒビターは、平滑筋収縮を感知できるほど阻害しない、請求項11〜29のいずれか1項に記載の方法。
- 前記方法は、前記骨格筋ミオシンIIインヒビターを投与する前および投与した後に、前記被験体の平滑筋収縮または前記平滑筋収縮からの筋力を測定する工程をさらに包含する、請求項30に記載の方法。
- 前記投与の前の前記被験体の平滑筋収縮は、前記投与の後の前記平滑筋収縮の10%以内である、請求項31に記載の方法。
- 前記骨格筋ミオシンIIのインヒビターは、インビトロアッセイにおいて、ATPase活性を阻害するが、心筋ミオシンS1 ATPaseを阻害しない、請求項10〜31のいずれか1項に記載の方法。
- 前記骨格筋ミオシンIIのインヒビターは、スルホンアミド、ヒドロキシクマリン、ピリダジノン、またはピロリジノンである、請求項10〜33のいずれか1項に記載の方法。
- 前記骨格筋ミオシンIIのインヒビターは、スルホンアミドである、請求項34に記載の方法。
- 前記骨格筋ミオシンIIのインヒビターは、必要に応じて置換されたN−ベンジル−p−トリル−スルホンアミドである、請求項35に記載の方法。
- 前記骨格筋ミオシンIIのインヒビターは、ピリダジノンである、請求項34に記載の方法。
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