JP2011522864A - 糖尿病患者における血管リモデリングおよび心血管疾患治療のための治療薬としての非アシル化グレリンおよび類似体 - Google Patents
糖尿病患者における血管リモデリングおよび心血管疾患治療のための治療薬としての非アシル化グレリンおよび類似体 Download PDFInfo
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Abstract
【選択図】なし
Description
AG グレリンまたはアシル化グレリン
UAG 非アシル化グレリンまたはDes−アシルグレリン
UAG(6〜13) 配列番号1の残基6〜13を有する非アシル化グレリン
GHSR 成長ホルモン分泌促進因子受容体
CAC 循環血中の血管新生細胞
EPC 血管内皮前駆細胞
AGE 最終糖化産物
BM 骨髄
VEGF 血管内皮増殖因子
FACS 蛍光活性化細胞選別
ROS 活性酸素種。
本発明の目的のため、次の用語を以下に定義する。本出願において、「グレリン」および「アシル化グレリン」または「AG」という用語は同義的に用い、同じ意味を有する。
配列番号2として示される配列番号1の残基1〜14((UAG1〜14);Gly−Ser−Ser−Phe−Leu−Ser−Pro−Glu−His−Gln−Arg−Val−Gln−Gln);
配列番号3として示される配列番号1の残基1〜18((UAG1〜18);Gly−Ser−Ser−Phe−Leu−Ser−Pro−Glu−His−Gln−Arg−Val−Gln−Gln−Arg−Lys−Glu−Ser);
配列番号4として示される配列番号1の残基1〜5((UAG1〜5);Gly−Ser−Ser−Phe−Leu);
配列番号5として示される配列番号1の残基17〜28((UAG17〜28);Glu−Ser−Lys−Lys−Pro−Pro−Ala−Lys−Leu−Gln−Pro−Arg);
配列番号6として示される配列番号1の残基6〜13((UAG6〜13);Ser−Pro−Glu−His−Gln−Arg−Val−Gln);
配列番号7として示される配列番号1の残基8〜13((UAG8〜13);Glu−His−Gln−Arg−Val−Gln)または
配列番号8として示される配列番号1の残基8〜12((UAG8〜12);Glu−His−Gln−Arg−Val)またはその類似体
を有し得る。
Algorithm: Needleman and Wunsch, J.Mol Biol.48: 443−453 (1970);
Comparison matrix: BLOSSUM62 from Hentikoff and Hentikoff, Proc. Natl. Acad. Sci. USA. 89:10915−10919 (1992); Gap Penalty: 12; Gap Length Penalty: 4
が挙げられる。
一態様では、本発明は、心血管疾患もしくは虚血性疾患発症リスクのある患者または発症患者などの被験体を治療するための方法を提供する。本発明は、被験体の血管リモデリングおよび/もしくは新血管形成を改善するための方法も提供する。さらなる一態様では、本発明は、被験体のCAC数を増加させるおよびCAC機能を改善するための方法を提供する。本発明は、生着を改善する、より詳細には移植(例えば、組織または臓器または任意のその一部の)関連もしくは移植後の生着を改善するための方法も提供する。本発明は、創傷治癒を改善し、生着を改善するおよび/または組織工学を促進するための方法も提供する。
下記に提示する実験およびデータ分析において、心血管リスクまたは疾患状況の再現を、糖尿病環境においていくつかの実験を実施することによって行なった。得られたデータから、CAC生体機能障害に関連することが確定されている、または確定され得る他の生理状態または環境を推定し得ることを当業者は理解するであろう。
I. UAGはCACを酸化ストレスから保護する
酸化ストレスは、糖尿病に関連した組織損傷(参考文献21)および内皮損傷において主要な役割を担い、主に活性酸素種(ROS)産生に依存する。UAGまたはAGが内皮細胞をアポトーシスから保護するという知見(参考文献8)から、CAC生物学に対する両グレリンアイソフォームの効果の検討に至った。
DNA損傷だけでなく、ストレスに惹起されるシグナルも老化様成長停止を誘発する(参考文献30)。p53、p21、およびpRbは老化の主要な調節因子であり、一般的にROS産生が上流シグナルとみなされる。促進された老化発現は糖尿病患者由来のEPC中に検出され得ることが既に示されている(参考文献22)。上記のデータにより、ROS産生が促進された老化発現に変わるか否か、およびUAGがこの作用を救済できるか否かに関する検討に至った。
CACは生理的にBM内に存在し、微小環境変化に反応して循環血中に動員される。CAC動員障害は心血管リスク因子の保因患者において報告されている(参考文献19、31)。
IV. UAG処置は糖尿病性CAC機能障害を救済する
新たに報告されたデータは、前駆細胞は、既存の血管構造に組み込まれて新生血管を形成し、血流を改善できることを示す(参考文献33)。UAGで処置した糖尿病患者から採取したCACがそれらの血管能を救済するか否かを検討するため、新規の血管形成をインビボでアッセイした。この目的のため、未処置もしくはUAG処置患者から採取し、IL−3およびCSFEで標識したCACを含むマトリゲルプラグをSCIDマウスに注射し、注射15日後にマトリゲルプラグを回収して免疫組織化学により分析した。結果(図4Eに報告)は、これらの標識された細胞の多くが、報告されているとおり、それらの内腔中赤血球によって機能性血管を形成したことを示す(図4E、パネルb(右))。一方、機能性血管は、未処置患者から採取したCACを使用した場合には検出できなかった(図4E、パネルa(左))。新生血管が宿主起源の血管性細胞由来である可能性を排除するために、免疫蛍光アッセイを、抗ヒトHLAクラスIおよび抗マウスMHC−II抗体を用いて実施した。大部分の血管がヒトHLAクラスI陽性細胞で覆われていることが認められた(図4F)。したがって、これらのデータにより、UAG処置はCACの利用能および血管リモデリング能力を改善するというさらなる証拠が得られた。
CAC膜上のUAGの特異的結合部位の存在は、かかる結合部位に対しての、100nM非標識UAG(1〜28)の[125I−Tyr4]−UAG(0.25nM)との競合能力を検討することによって調査した。結合特異性も、100nM AG(1〜28)(アシル化グレリン)、UAG(28〜1)、生物学的不活性グレリン類似体、および合成UAG(6〜13)−NH2断片の存在下で試験した。この競合結合試験の結果(図5A)は、[125I−Tyr4]−UAGのCAC膜との結合はUAG(1〜28)とUAG(6〜13)の両方に阻害されたが、AG(1〜28)またはUAG(28〜1)には阻害されなかったことを明らかにした。[125I−Tyr4]−UAGの特異結合(UAG不在下、対照、およびUAG存在下の結合間の差として計算)は対照値の約75%(P<0.001)を示し、2つの異なる細胞調製物由来の新鮮CAC膜(0.25および0.26fmol)または凍結融解CAC膜(0.20および0.33fmol)のいずれかで検出された。
患者および対照:6人の2型糖尿病患者(性別、男/女5/1例;HbA1c値8±1.2%;年齢62.8±12.46歳;BMI値27.1±3.22、クレアチニン値1.04±0.20mg/dL;腰囲(cm)98.2±7.52、総コレステロール値192±50mmol/L、HDLコレステロール値46±13.98mmol/L、LDLコレステロール値113±39.77mmol/L、トリグリセリド値157.5±54.23、空腹時グルコース値126±19.04mg/dL、網膜症なし、高血圧3人、血圧141/87mmHg;Chol/apoB値1.3±0.1)から採血した。すべての患者は食事療法のみで治療された(糖尿病患者による他剤の使用はなかった)。8人の血液ドナーを対照として用いた(性別、男/女4/4例;年齢26.6±4.65歳;BMI値21.14±8.08、クレアチニン値0.96±0.063mg/dL、総コレステロール値162.13±10.79mmol/L、HDLコレステロール値49±10.4mmol/L、LDLコレステロール値86.25±17.72mmol/L、トリグリセリド値132.13±27.10、網膜症なし、高血圧例なし:血圧125/70mmHg、Chol/apoB値1.6±0.1)。
・UAG(0〜12時間目の12時間、3.0μg/kg/時間iv注入);
・等張生理食塩水(0〜12時間目注入)
。
すべての試験の実施を、一晩絶食後、留置カテーテルを前腕静脈中に配置して等張生理食塩水を遅い速度で注入30分後の午前8時半〜9時に開始した。血液試料を0時間、6時間および12時間後に採取した。
糖尿病および対照マウス:マウスを4群に分けた。各群で測定した血漿グルコース値およびインスリン値を報告する。16匹の6週齢ob/obマウス(血糖値600±45mg/dL、インスリン値5.5±0.9ng/mL);16匹のC56BL6/J野生型マウス(血糖値150±18.2mg/dL、インスリン値1±0.05ng/mL);10匹の7週齢NOD/SCIDマウス(血糖値164±12.9mg/dL、インスリン値1.2±0.12ng/mL);10匹の17週齢NOD/SCIDマウス(血糖値536±36.3mg/dL、インスリン値4.85±0.74ng/mL)。動物処置はGuide for Care and Use of Laboratory Resources(National Institutes of Health publication no.93−23, revised 1985)に準じた。
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Claims (50)
- 配列番号1に示されるアミノ酸配列を含むポリペプチドまたは配列番号1の生物学的活性を有するその断片もしくはその類似体を治療有効量で被験体に投与することを含む、被験体の心血管疾患を治療するための方法。
- 血管リモデリングおよび/または新血管形成を改善するための、請求項1に記載の方法。
- 循環血中の血管新生細胞(CAC)数を増加させるおよび/またはCAC機能を改善するための、請求項1または2に記載の方法。
- CACを酸化ストレスから保護するための、請求項3に記載の方法。
- CAC動員を改善するための、請求項3または4に記載の方法。
- CAC老化を低減するための、請求項3〜5のいずれか1項に記載の方法。
- 前記ポリペプチドが約0.001μg/kg〜約10mg/kgの範囲で変わる用量で投与される、請求項1〜6のいずれか1項に記載の方法。
- 前記心血管疾患が1型または2型糖尿病に関連している、請求項1〜7のいずれか1項に記載の方法。
- 前記心血管疾患が肥満に関連している、請求項1〜8のいずれか1項に記載の方法。
- 前記心血管疾患が代謝症候群に関連している、請求項1〜8のいずれか1項に記載の方法。
- 前記心血管疾患がアテローム硬化性血管変性症に関連している、請求項1〜8のいずれか1項に記載の方法。
- 前記その断片が配列番号1の残基8〜12またはその類似体を含む、請求項1〜11のいずれか1項に記載の方法。
- 前記その断片が配列番号1の残基6〜13またはその類似体を含む、請求項1〜11のいずれか1項に記載の方法。
- 前記その断片が配列番号6、配列番号7、配列番号8およびその類似体からなる群から選択されるアミノ酸配列を有する、請求項1〜11のいずれか1項に記載の方法。
- 前記その断片が配列番号6のアミノ酸配列からなる、請求項1〜11のいずれか1項に記載の方法。
- 前記被験体がヒトである、請求項1〜15のいずれか1項に記載の方法。
- 配列番号1に示されるアミノ酸配列を含むポリペプチド、または配列番号1の生物学的活性を有するその断片もしくはその類似体を治療有効量で被験体に投与することを含む、被験体の循環血中の血管新生細胞(CAC)数を増加させるおよび/またはCAC機能を改善するための方法。
- CACを酸化ストレスから保護するための、請求項17に記載の方法。
- CAC動員を改善するための、請求項17または18に記載の方法。
- CAC老化を低減するための、請求項17〜19のいずれか1項に記載の方法。
- 血管リモデリングおよび/または新血管形成を改善するための、請求項17〜20のいずれか1項に記載の方法。
- 前記被験体が心血管疾患発症リスクのあるまたは心血管疾患を有している、請求項17〜21のいずれか1項に記載の方法。
- 前記被験体が1型または2型糖尿病である、請求項17〜22のいずれか1項に記載の方法。
- 前記ポリペプチドが約0.001μg/kg〜約10mg/kgの範囲で変わる用量で投与される、請求項17〜23のいずれか1項に記載の方法。
- 前記その断片が配列番号1の残基8〜12またはその類似体を含む、請求項17〜24のいずれか1項に記載の方法。
- 前記その断片が配列番号1の残基6〜13またはその類似体を含む、請求項17〜24のいずれか1項に記載の方法。
- 前記その断片が配列番号6、配列番号7、配列番号8およびその類似体からなる群から選択されるアミノ酸配列を有する、請求項17〜24のいずれか1項に記載の方法。
- 前記その断片が配列番号6のアミノ酸配列からなる、請求項17〜24のいずれか1項に記載の方法。
- 配列番号1に示される配列を含むポリペプチド、または配列番号1の生物学的活性を有するその断片もしくはその類似体を治療有効量で被験体に投与することを含む、被験体の血管リモデリングおよび/もしくは新血管形成を改善するための方法。
- 循環血中の血管新生細胞(CAC)数を増加させるおよび/またはCAC機能を改善するための、請求項29に記載の方法。
- 前記ポリペプチドが約0.001μg/kg〜約10mg/kgの範囲で変わる用量で投与される、請求項29または30に記載の方法。
- 前記その断片が配列番号1の残基8〜12またはその類似体を含む、請求項29〜31のいずれか1項に記載の方法。
- 前記その断片が配列番号1の残基6〜13またはその類似体を含む、請求項29〜31のいずれか1項に記載の方法。
- 前記その断片が配列番号6、配列番号7、配列番号8およびその類似体からなる群から選択されるアミノ酸配列を有する、請求項29〜31のいずれか1項に記載の方法。
- 前記その断片が配列番号6のアミノ酸配列からなる、請求項29〜31のいずれか1項に記載の方法。
- 治療有効量のポリペプチドを製薬上許容される担体と共に含む、心血管疾患の治療における使用のための医薬組成物であって、前記ポリペプチドが、配列番号1に示されるアミノ酸配列を含むポリペプチド、または配列番号1の生物学的活性を有するその断片もしくはその類似体である、上記組成物。
- 被験体の心血管疾患の治療における使用のための、配列番号1に示されるアミノ酸配列を含む単離されたポリペプチド、または配列番号1の生物学的活性を有するその断片もしくはその類似体。
- 被験体の循環血中の血管新生細胞(CAC)数を増加させるおよび/もしくはCAC機能を改善するための、配列番号1に示されるアミノ酸配列を含む単離されたポリペプチド、または配列番号1の生物学的活性を有するその断片もしくはその類似体。
- 被験体の血管リモデリングおよび/もしくは新血管形成を改善するための、配列番号1に示されるアミノ酸配列を含む単離されたポリペプチド、またはその断片もしくはその類似体。
- 被験体の創傷治癒を改善するための、配列番号1に示されるアミノ酸配列を含む単離されたポリペプチド、またはその断片もしくはその類似体。
- 前記被験体が糖尿病性潰瘍に罹患している、請求項40に記載の単離されたポリペプチド。
- 移植関連生着を改善するための、配列番号1に示されるアミノ酸配列を含む単離されたポリペプチド、またはその断片もしくはその類似体。
- 前記生着が臓器移植後の生着である、請求項42に記載のポリペプチド。
- 組織工学における使用のための、配列番号1に示されるアミノ酸配列を含む単離されたポリペプチド、またはその断片もしくはその類似体。
- 被験体の心血管疾患の治療のための、治療有効量の配列番号1に示されるアミノ酸配列を含むポリペプチドまたは配列番号1の生物学的活性を有するその断片もしくはその類似体の使用。
- 被験体の心血管疾患治療のための医薬の調製における、治療有効量の配列番号1に示されるアミノ酸配列を含むポリペプチドまたは配列番号1の生物学的活性を有するその断片もしくはその類似体の使用。
- 被験体の循環血中の血管新生細胞(CAC)数を増加させるおよび/もしくはCAC機能を改善するための、治療有効量の配列番号1に示されるアミノ酸配列を含むポリペプチド、または配列番号1の生物学的活性を有するその断片もしくはその類似体の使用。
- 被験体の循環血中の血管新生細胞(CAC)数を増加させるおよび/もしくはCAC機能を改善するための医薬の調製における、治療有効量の配列番号1に示されるアミノ酸配列を含むポリペプチド、または配列番号1の生物学的活性を有するその断片もしくはその類似体の使用。
- 被験体の血管リモデリングおよび/もしくは新血管形成を改善するための、治療有効量の配列番号1に示される配列を含むポリペプチド、または配列番号1の生物学的活性を有するその断片もしくはその類似体の使用。
- 被験体の血管リモデリングおよび/もしくは新血管形成を改善するための医薬の調製における、治療有効量の配列番号1に示される配列を含むポリペプチド、または配列番号1の生物学的活性を有するその断片もしくはその類似体の使用。
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US20140378380A1 (en) | 2013-06-21 | 2014-12-25 | Alizé Pharma SAS | Use of unacylated ghrelin, fragments and analogs thereof as antioxidant |
US10301609B2 (en) | 2014-04-29 | 2019-05-28 | Mayo Foundation For Medical Education And Research | Butyrylcholinesterases having an enhanced ability to hydrolyze acyl ghrelin |
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US20110160121A1 (en) | 2011-06-30 |
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US20100016226A1 (en) | 2010-01-21 |
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