JP5552048B2 - 加齢性黄斑変性を治療するためのアルファコネキシンc末端(act)ペプチド - Google Patents
加齢性黄斑変性を治療するためのアルファコネキシンc末端(act)ペプチド Download PDFInfo
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Description
本出願は、参照によりその全体が本明細書に組み込まれる、2007年6月21日に出願された米国仮出願第60/945,493号の利益を主張する。
本発明は、米国立衛生研究所により授与された助成金第EY13520号の下での政府援助により行われた。政府は本発明における一定の権利を有する。
アルファコネキシンのカルボキシ末端アミノ酸配列(本明細書では、アルファコネキシンカルボキシ末端(ACT)ポリペプチドとも称する)またはその保存的変異体を含む単離ポリペプチドが、開示される方法での使用のために開示される。提供される方法のACTポリペプチドは、これらのペプチド教示について、参照によりその全体が本明細書に組み込まれる、国際特許公開WO/2006/069181において開示されている。
000. Cancer Res. 60、6551-6556)のアミノ酸配列をさらに含み得る。提供されるポリペプチドは、BGSC(ビス−グアニジニウム−スペルミジン−コレステロール)またはBGTC(ビス−グアニジニウム−トレン−コレステロール)をさらに含み得る(Vigneron, J.P. et al. 1998. Proc. Natl. Acad. Sci. USA. 93、9682-9686)。前出の参考文献は、細胞内部移行ベクターおよび配列の教示について、参照によりその全体が本明細書に組み込まれる。今日既知であるかまたは後に同定される他の任意の内部移行配列を、本発明のペプチドと組み合わせることができる。
本明細書では、本明細書ではアルファコネキシンカルボキシ末端(ACT)ポリペプチドとも称する、アルファコネキシンカルボキシ末端アミノ酸配列またはその保存的変異体を含むポリペプチドを対象に投与することを含む、上皮透過性および/または新生血管形成(例えば、血管新生または血管発生)を伴う病態の治療または予防のための組成物および方法が提供される。
また、対象における黄斑変性を治療または予防する方法であって、対象にアルファコネキシンカルボキシ末端アミノ酸配列またはその保存的変異体を含む治療有効量の単離ポリペプチドを投与することを含む方法も提供される。
また、対象における糖尿病性網膜症を治療または予防する方法であって、前記糖尿病性網膜症を有するかまたはこれを有する危険性を示す対象を同定することと、対象の網膜に本明細書で開示されるポリペプチドを投与することとを含む方法も提供される。
また、対象における未熟児網膜症(ROP)を治療または予防する方法であって、前記ROPを有するかまたはこれを有する危険性を示す対象を同定することと、対象の網膜に本明細書で開示されるポリペプチドを投与することとを含む方法も提供される。
「血管透過性」とは、小分子(イオン、水、栄養物)または全細胞(炎症部位への途上におけるリンパ球)さえもが血管壁を通過する能力を指す。血管壁は、単層の内皮細胞により裏打ちされている。内皮細胞間のギャップ(細胞間結合)は、組織の種類および生理学的状態に応じて厳密に調節されている。
血管新生および血管新生関連疾患は、細胞増殖により深く影響される。本明細書で用いられる「血管新生」という用語は、組織または臓器内への新血管の発生を意味する。正常な生理学的状態下において、ヒトまたは動物が血管新生を経験するのは、極めて特殊な限定された状況に限られる。例えば、血管新生は通常、創傷の治癒、黄体、子宮内膜、および胎盤の胎児性および胚性の発達および形成において観察される。本明細書において、「内皮」という用語は、漿膜腔、リンパ管、および血管を裏打ちする薄層の扁平細胞として定義される。これらの細胞が「内皮細胞」と定義される。「内皮阻害活性」という用語は、分子が血管新生を阻害する能力一般を意味する。内皮細胞増殖の阻害はまた、結果として血管新生の阻害ももたらす。
開示される化合物および組成物は、任意の適切な方式で投与することができる。投与方式は、例えば、局所治療または全身治療のいずれが望ましいのか、また、治療される領域に基づいて選択される。例えば、組成物は、経口投与、非経口投与(例えば、標的となる特定の組織、臓器、および身体部分への注射、静脈内注射、眼内注射、腫瘍内注射、関節内注射、心内注射、腹腔内注射、または筋肉内注射)、吸入投与、体外投与、局所投与(経皮投与、眼内投与、膣内投与、直腸内投与、鼻腔内投与を含む)などにより投与することができる。
本明細書で開示される組成物および開示される方法を実施するのに必要な組成物は、別段に特記しない限り、その特定の試薬または化合物について当業者に知られる任意の方法を用いて作製することができる。
別段に定義しない限り、本明細書で用いられる技術用語および科学用語は、開示される方法および組成物が帰属する当技術分野の当業者により一般的に理解される意味と同じ意味を有する。本方法および組成物の実施または試験においては、本明細書で説明される方法および材料と同様または同等の任意の方法および材料を用いることができるが、特に有用な方法、機器、および材料は、説明される通りである。本明細書で引用される刊行物およびそれについてそれらが引用される材料は、参照により本明細書に具体的に組み込まれる。本明細書における一切の記載を、先願発明のために、本発明が、このような開示に先行する権利を有さないことの承認として理解すべきではない。参照が先行技術を構成するという承認がなされるわけではない。参考文献の議論は、それらの著者が主張する内容を述べるものであり、出願者は、引用される文献の正確性および適切性に異議を唱える権利を留保する。
図1に示す通り、ARPE−19細胞中において、アルファコネキシンカルボキシ末端(ACT)ポリペプチドACT1により、VEGFに誘導されるTERの低下が防止される。単層ARPE19細胞(不死化ヒトRPE細胞)を用いる経上皮抵抗(TER)測定は、VEGFにより急速な低下がもたらされ、これがACTペプチドによる細胞の前処置により遮断されることが示された。したがって、理論に拘束されることは望まないが、ACTペプチドによる密着結合タンパク質の安定化により、密着結合分解の喪失およびこれによるRPE/ブルッフ膜への損傷を防止することができる。
マウスの眼の角膜に対する、0.05%のBrij−78を含有する溶液中におけるACT1ペプチドの適用の結果、適用の20および40分後において前房内液(すなわち、房水)中に検出可能なレベルのACT1がもたらされた(図2)。20および40分後の後眼房に由来する体液、すなわち、硝子体液中でもまた、ウェスタンブロット法により低レベルのACT1を検出することができた。
サラジン/ケタミン0.2mLの腹腔内注射により、3匹のCD1マウスに麻酔をかけた。通常の生理食塩液と0.05%のBrij−78とを含有する1mMのACT1ペプチド10μLを両眼の角膜表面に静かに滴下し、20または40分間にわたり透過させた。対照マウスには、通常の生理食塩液中に0.05%のBrij−78を用いた。CO2チャンバー内でマウスを安楽死させ、20分後、40分後(対照マウスは20分後)に頸椎脱臼させた。眼を除去し、PBS中ですすいだ。前房をわずかに切開し、房水(約10μL)を試験管に移し、ドライアイス入りのエタノール浴中で瞬時凍結させた。全試料を2倍濃度の試料ローディングバッファー中で溶解させ、10〜20%のトリス−トリシンゲル上にロードした。PDVF膜にゲルを転写し、RBTシグマ抗CX43 CT抗体(1:10000)およびヤギ抗RBT AP二次抗体(1:15000)を用いて染色し、<10kDaにおいてACT1バンドを明らかにした。
Claims (7)
- 対象における黄斑変性を治療または予防するための医薬組成物であって、配列番号1、配列番号2、配列番号3、配列番号4、及び配列番号5からなる群より選択されるアルファコネキシンアミノ酸配列からなる単離ポリペプチドを含む医薬組成物。
- 前記ポリペプチドが、配列番号2のアミノ酸配列からなる、請求項1に記載の医薬組成物。
- 対象における黄斑変性を治療または予防するための医薬組成物であって、配列番号1、配列番号2、配列番号3、配列番号4、及び配列番号5で表されるアミノ酸配列からなる群より選択されるアルファコネキシンアミノ酸配列と、
細胞内部移行配列と、
からなる単離ポリペプチドを含む医薬組成物。 - 前記細胞内部移行配列が、アンテナペディア、TAT、HIV−Tat、ペネトラチン、Antp−3A(Antp変異体)、ブフォリンII、トランスポータン、MAP(両親媒性モデルペプチド)、K−FGF、Ku70、プリオン、pVEC、Pep−1、SynB1、Pep−7、HN−1、BGSC(ビス−グアニジニウム−スペルミジン−コレステロール)、およびBGTC(ビス−グアニジニウム−トレン−コレステロール)からなる群から選択されるタンパク質のアミノ酸配列を含む、請求項3に記載の医薬組成物。
- 前記細胞内部移行配列がアンテナペディアであり、配列が配列番号7のアミノ酸配列を含む、請求項3又は4に記載の医薬組成物。
- 対象における黄斑変性を治療または予防するための医薬組成物であって、
配列番号8、配列番号9、配列番号10、配列番号11、および配列番号12からなる群から選択されるアミノ酸配列、又は
配列番号8、配列番号9、配列番号10、配列番号11、および配列番号12からなる群から選択されるアミノ酸配列と少なくとも90%の配列同一性を有するアミノ酸配列
からなる単離ペプチドを含む医薬組成物。 - 前記ポリペプチドが、配列番号9、または配列番号9と少なくとも90%の配列同一性を有するアミノ酸配列からなる、請求項6に記載の医薬組成物。
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PCT/US2008/067944 WO2008157840A2 (en) | 2007-06-21 | 2008-06-23 | Alpha connexin c-terminal (act) peptides for treating age-related macular degeneration |
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US9408381B2 (en) | 2004-12-21 | 2016-08-09 | Musc Foundation For Research Development | Alpha Connexin c-Terminal (ACT) peptides for use in transplant |
US20100286762A1 (en) * | 2009-03-18 | 2010-11-11 | Musc Foundation For Research Development | Compositions and Methods for Ameliorating Clinical Electrical Disturbances |
NZ629769A (en) | 2012-03-01 | 2016-09-30 | Firststring Res Inc | Topical gels containing alpha connexin c-terminal (act) peptides |
US9345744B2 (en) | 2012-04-25 | 2016-05-24 | Musc Foundation For Research Development | Peptide-based collagen modulators for wound healing and tissue repair |
US10981961B2 (en) * | 2013-03-11 | 2021-04-20 | University Of Florida Research Foundation, Incorporated | Delivery of card protein as therapy for occular inflammation |
ES2911714T3 (es) | 2014-03-11 | 2022-05-20 | Univ Florida | Proteína M013 expresada por AAV como un terapéutico antiinflamatorio para su uso en un método de tratamiento de enfermedad ocular inflamatoria |
HK1243457A1 (zh) * | 2014-08-22 | 2018-07-13 | Auckland Uniservices Ltd | 通道調節劑 |
CN107109410B (zh) | 2014-08-22 | 2021-11-02 | 奥克兰联合服务有限公司 | 通道调节剂 |
ES2804039A1 (es) * | 2019-07-30 | 2021-02-02 | Fund Profesor Novoa Santos | Fragmentos peptidicos de cx43 para su uso como agentes senoliticos |
WO2022087396A1 (en) * | 2020-10-22 | 2022-04-28 | Firststring Research, Inc. | Peptide formulations and ophthalmic uses thereof |
WO2023220756A2 (en) * | 2022-05-13 | 2023-11-16 | Character Biosciences, Inc. | Therapeutic lipid processing compositions and methods for treating age-related macular degeneration |
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FR2739621B1 (fr) * | 1995-10-05 | 1997-12-05 | Centre Nat Rech Scient | Peptides utilisables comme vecteurs pour l'adressage intracellulaire de molecules actives |
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US6867283B2 (en) * | 2001-05-16 | 2005-03-15 | Technion Research & Development Foundation Ltd. | Peptides capable of binding to MHC molecules, cells presenting such peptides, and pharmaceutical compositions comprising such peptides and/or cells |
US20050053918A1 (en) * | 2001-05-16 | 2005-03-10 | Technion Research & Development Foundation Ltd. | Method of identifying peptides capable of binding to MHC molecules, peptides identified thereby and their uses |
US6685971B2 (en) * | 2001-06-28 | 2004-02-03 | Rongxiang Xu | Method and composition for repairing and promoting regeneration of mucosal tissue in the gastrointestinal tract |
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