JP6921006B2 - 老化関連症状を治療するための方法および組成物 - Google Patents
老化関連症状を治療するための方法および組成物 Download PDFInfo
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Images
Classifications
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A—HUMAN NECESSITIES
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Description
上記で要約したように、本発明の態様には、成体哺乳動物における老化関連症状を治療する方法が含まれる。老化関連症状は、多数の異なる態様で、例えば老化関連認知障害および/または生理的障害として、例えば、これらに限定されないが細胞傷害、組織損傷、臓器機能不全、老化関連寿命短縮および発癌などの身体の中枢または末梢器官への損傷の形で現れ得、関心対象の特定器官および組織には、これらに限定されないが、皮膚、ニューロン、筋肉、膵臓、脳、腎臓、肺、胃、腸、脾臓、心臓、脂肪組織、精巣、卵巣、子宮、肝臓および骨が含まれ、あるいは、神経可塑性の低下などの形で現れ得る。
MGAAARTLRL ALGLLLLATL LRPADACSCS PVHPQQAFCN ADVVIRAKAV
60 70 80 90 100
SEKEVDSGND IYGNPIKRIQ YEIKQIKMFK GPEKDIEFIY TAPSSAVCGV
110 120 130 140 150
SLDVGGKKEY LIAGKAEGDG KMHITLCDFI VPWDTLSTTQ KKSLNHRYQM
160 170 180 190 200
GCECKITRCP MIPCYISSPD ECLWMDWVTE KNINGHQAKF FACIKRSDGS
210 220
CAWYRGAAPP KQEFLDIEDP (SEQ ID NO:01)
MAPFEPLASG ILLLLWLIAP SRACTCVPPH PQTAFCNSDL VIRAKFVGTP
60 70 80 90 100
EVNQTTLYQR YEIKMTKMYK GFQALGDAAD IRFVYTPAME SVCGYFHRSH
110 120 130 140 150
NRSEEFLIAG KLQDGLLHIT TCSFVAPWNS LSLAQRRGFT KTYTVGCEEC
160 170 180 190 200
TVFPCLSIPC KLQSGTHCLW TDQLLQGSEK GFQSRHLACL PREPGLCTWQ
SLRSQIA (SEQ ID NO:02)
MTPWLGLIVL LGSWSLGDWG AEACTCSPSH PQDAFCNSDI VIRAKVVGKK
60 70 80 90 100
LVKEGPFGTL VYTIKQMKMY RGFTKMPHVQ YIHTEASESL CGLKLEVNKY
110 120 130 140 150
QYLLTGRVYD GKMYTGLCNF VERWDQLTLS QRKGLNYRYH LGCNCKIKSC
160 170 180 190 200
YYLPCFVTSK NECLWTDMLS NFGYPGYQSK HYACIRQKGG YCSWYRGWAP
210
PDKSIINATD P (SEQ ID NO:03)
MPGSPRPAPS WVLLLRLLAL LRPPGLGEAC SCAPAHPQQH ICHSALVIRA
60 70 80 90 100
KISSEKVVPA SADPADTEKM LRYEIKQIKM FKGFEKVKDV QYIYTPFDSS
110 120 130 140 150
LCGVKLEANS QKQYLLTGQV LSDGKVFIHL CNYIEPWEDL SLVQRESLNH
160 170 180 190 200
HYHLNCGCQI TTCYTVPCTI SAPNECLWTD WLLERKLYGY QAQHYVCMKH
210 220
VDGTCSWYRG HLPLRKEFVD IVQP (SEQ ID NO:04)
本方法は、個体の認知能力の障害などの、老化関連障害およびそれに関連する症状を治療、さらには予防することにおける使用を見出す。老化関連認知障害に罹患しているか、またはそれを発症するリスクがある個体には、約50歳以上、例えば、60歳以上、70歳以上、80歳以上、90歳以上、通常は100歳以下、すなわち、例えば50歳、55歳、60歳、65歳、70歳、75歳、80歳、85歳、90歳、95歳または約100歳などの約50歳〜100歳の間であり、軽度認知障害(MCI)などの自然老化プロセスに関連する認知障害に罹患する個体、および、約50歳以上、例えば、60歳以上、70歳以上、80歳以上、90歳以上、通常は100歳以下、すなわち、例えば50歳、55歳、60歳、65歳、70歳、75歳、80歳、85歳、90歳、95歳または約100歳などの約50歳〜90歳の間であり、認知障害の症候をまだ示し始めていない個体が含まれる。自然老化による認知障害の例には、以下が含まれる。
本発明の活性薬剤は、単独で、または追加の、すなわち第2の活性薬剤と組み合わせて、対象に投与することができる。このように、いくつかの場合では、本方法は、対象に少なくとも1つのさらなる化合物を投与することをさらに含む。任意の便利な薬剤を利用し得る。例えば、TIMP活性剤を単独で、または、例えば、コリンエステラーゼ阻害剤(例えば、ドネペジル、リバスチグミン、ガランタミン、タクリン)、メマンチン、ビタミンE、シタロプラム(セレクサ)、フルオキセチン(プロザック)、パロキセチン(パキシル)、セルトラリン(ゾロフト)、トラゾドン(デシレル)、ロラゼパム(アチバン)、オキサゼパム(セラックス)、アリピプラゾール(エビリファイ)、クロザピン(クロザリル)、ハロペリドール(ハルドール)、オランザピン(ジプレクサ)、クエチアピン(セロクエル)、リスペリドン(リスパダール)およびジプラシドン(ジオドン);非TIMPポリペプチド活性剤;例えばケモカイン(C−Cモチーフ)リガンド2(CCL2)(すなわち、MCP1);C−Cモチーフケモカイン11(すなわち、走化性タンパク質またはエオタキシン−1);顆粒球マクロファージコロニー刺激因子(GM−CSF)(すなわち、コロニー刺激因子2またはCSF2)などの老化関連症状の治療に用いられる薬物のような、1つ以上の他の薬物と組み合わせて、供給することができる。
また、本化合物の医薬製剤も提供される。本化合物は、対象への投与のための様々な製剤に組み込むことができる。より具体的には、本発明の化合物は、適切な薬学的に許容される担体または希釈剤と組み合わせることによって医薬組成物に製剤することができ、固体、半固体、液体または気体形態の製剤、例えば錠剤、カプセル剤、粉末、顆粒、軟膏、溶液、坐剤、注射剤、吸入剤およびエアロゾルに製剤され得る。製剤は、経口、頬内、直腸、非経口、腹腔内、皮内、経皮、気管内投与などの多数の異なる経路を介した投与のために設計され得る。
また、上述のように記載されたもののような、方法の実施形態の実施で使用されるキットおよびシステムも提供される。本明細書で使用される「システム」という用語は、本方法を実施する目的で一緒にされた、単一の組成物または異なる組成物中に存在する2つ以上の異なる活性物質の集まりを指す。「キット」という用語は、パッケージングされた活性剤(複数可)を指す。例えば、本方法を実施するためのキットおよびシステムは、1つまたは複数の医薬製剤を含み得る。そのようなものとして、特定の実施形態では、キットは、1つ以上の単位用量として存在する単一の医薬組成物を含み得、組成物は、1つ以上の発現/活性阻害剤化合物を含み得る。さらに他の実施形態において、キットは、それぞれ異なる活性化合物を含有する2つ以上の別個の医薬組成物を含み得る。
老齢野生型(C57Bl/6J)マウスの腹腔内注射により、組換えTIMP2タンパク質を50μg/kgの濃度で1週間にわたって4回送達した。処置されたマウスの脳は、活性ニューロン、すなわち海馬の歯状回部分領域において前初期遺伝子c−Fosを発現するニューロンのレベル上昇を明らかにした。TIMP2の8回(長期)腹腔内注射(50μg/kg)を、バーンズ迷路、ネスティングおよび恐怖条件付け評価の前に、老齢野生型マウスに1日おきに与えた。行動試験により、TIMP2処置マウスの3つのタスク全てにおいて有意に改善された効能が明らかになった。TIMP2の7回(長期)腹腔内注射(50μg/kg)を、老齢野生型マウスに1日おきに単独で、または別の認知促進因子、CSF2と組み合わせて与えた。TIMP2およびTIMP2+CSF2マウスの脳は、歯状回におけるc−Fos+(活性)ニューロンのレベルの有意な上昇を示した。
1.老化関連症状についての成体哺乳動物の治療方法であって、哺乳動物におけるTIMP活性を、老化関連症状について成体哺乳動物を治療するために十分な程度に増強することを含む方法。
2.TIMP活性が、TIMP1、TIMP2、TIMP3またはTIMP4活性である、付記1に記載の方法。
3.TIMP活性がTIMP2活性である、付記2に記載の方法。
4.全身性TIMP活性を増強することを含む、付記1〜3のいずれか一つに記載の方法。
5.哺乳動物におけるTIMP活性剤の全身レベルを増加させることを含む、付記1〜4のいずれか一つに記載の方法。
7.TIMP活性剤がTIMPポリペプチドまたはその模倣物である、付記6に記載の方法。
8.TIMP活性剤がTIMPポリペプチドである、付記7に記載の方法。
9.TIMPポリペプチドが、配列ID番号1〜4のいずれかSEQ ID NOSと少なくとも60%同一である配列を有する、付記8に記載の方法。
10.内因性TIMPコード配列の発現を増強することを含む、付記1〜5のいずれか一つに記載の方法。
12.哺乳動物が霊長類である、付記1〜11のいずれか一つに記載の方法。
13.霊長類がヒトである、付記12に記載の方法。
14.成体哺乳動物が老齢哺乳動物である、付記1〜13のいずれか一つに記載の方法。
15.老齢哺乳動物が60歳以上のヒトである、付記14に記載の方法。
17. 成体哺乳動物が老化関連疾患症状に罹患している、付記1〜16のいずれか一つに記載の方法。
18. 老化関連疾患症状が認知低下疾患症状である、付記1〜17のいずれか一つに記載の方法。
本発明は、国立衛生研究所により授与された契約AG045034に基づく政府の支援によってなされた。政府は本発明に一定の権利を有する。
35U.S.C.§119(e)に従って、本願は、2015年6月15日に出願された米国仮特許出願第62/175,981号の出願日の優先権を主張し、その開示は参照により本明細書に組み込まれる。
Claims (7)
- 認知障害または認知低下を含む老化関連症状についての成体哺乳動物を治療するために使用される医薬組成物であって、
TIMP2ポリペプチドもしくはそのフラグメント、または、TIMP2ポリペプチドをコードする核酸組成物もしくはそのフラグメントを含んでおり、
哺乳動物におけるTIMP2活性が、老化関連の認知障害または認知低下について成体哺乳動物を治療するために十分な程度に増強される
ことを特徴とする医薬組成物。 - 前記医薬組成物は、全身性TIMP2活性を増強することを特徴とする請求項1に記載の医薬組成物。
- 前記医薬組成物は、哺乳動物におけるTIMP2ポリペプチドまたはそのフラグメントの全身レベルを増加させることを特徴とする請求項1または2に記載の医薬組成物。
- 前記医薬組成物は、TIMP2ポリペプチドを含むことを特徴とする請求項1〜3のいずれか一項に記載の医薬組成物。
- 哺乳動物が霊長類であることを特徴とする請求項1〜4のいずれか一項に記載の医薬組成物。
- 成体哺乳動物が老齢哺乳動物であることを特徴とする請求項1〜5のいずれか一項に記載の医薬組成物。
- 霊長類がヒトであることを特徴とする請求項5に記載の医薬組成物。
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