JPWO2014065347A1 - Hmgb1断片を利用した新規心筋梗塞の治療法 - Google Patents
Hmgb1断片を利用した新規心筋梗塞の治療法 Download PDFInfo
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- JPWO2014065347A1 JPWO2014065347A1 JP2014543334A JP2014543334A JPWO2014065347A1 JP WO2014065347 A1 JPWO2014065347 A1 JP WO2014065347A1 JP 2014543334 A JP2014543334 A JP 2014543334A JP 2014543334 A JP2014543334 A JP 2014543334A JP WO2014065347 A1 JPWO2014065347 A1 JP WO2014065347A1
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- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4718—Cytokine-induced proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Abstract
Description
[1]
HMGB1断片ペプチドを含有する、心筋梗塞を治療するために用いられる医薬組成物。
[2]
前記HMGB1断片ペプチドが、配列番号:3のアミノ酸配列を含むペプチドである、[1]の医薬組成物。
[3]
前記HMGB1断片ペプチドが、配列番号:3のアミノ酸配列からなるペプチドである、[1]の医薬組成物。
[4]
HMGB1断片ペプチドを投与する工程を含む、心筋梗塞の治療方法。
[5]
前記HMGB1断片ペプチドが、配列番号:3のアミノ酸配列を含むペプチドである、[4]の方法。
[6]
前記HMGB1断片ペプチドが、配列番号:3のアミノ酸配列からなるペプチドである、[4]の方法。
[7]
心筋梗塞を治療するために使用するHMGB1断片ペプチド。
[8]
前記HMGB1断片ペプチドが、配列番号:3のアミノ酸配列を含むペプチドである、[7]のHMGB1断片ペプチド。
[9]
前記HMGB1断片ペプチドが、配列番号:3のアミノ酸配列からなるペプチドである、[7]のHMGB1断片ペプチド。
[10]
HMGB1断片ペプチドを含有する、心筋梗塞を治療するために用いられる医薬の製造のための使用。
[11]
前記HMGB1断片ペプチドが、配列番号:3のアミノ酸配列を含むペプチドである、[10]の使用。
[12]
前記HMGB1断片ペプチドが、配列番号:3のアミノ酸配列からなるペプチドである、[10]の使用。
マウス急性期心筋梗塞モデルを用いてHMGB1タンパク質の断片ペプチド(1-44)の全身投与による治療効果を、心臓生理学的・病理組織学的・分子生物学的手法を用いて包括的に評価する。
骨髄キメラマウスは3週齢のマウス(C57BL6-CAG-GFPトランスジェニックマウス)の大腿/下腿骨より骨髄細胞を採取し、骨髄細胞懸濁液を放射線照射後(10GY)の6週齢マウス(C57BL6)に尾静脈投与(300ΜL/MOUSE)することで作成した。骨髄移植後60日に全身麻酔下仰臥位で左第4肋間開胸を行い、冠動脈左前下行枝近位部を結紮し、広範囲心筋梗塞モデル(左冠動脈前下行枝/回旋枝閉塞モデル)を作成した。HMGB1タンパク質の低分子化の際、骨髄間葉系幹細胞動員活性の保持を考慮した上で、HMGB1タンパク質の断片ペプチド(1-44)を開発した。梗塞作成6、24、48、72、96h後に尾静脈よりHMGB1タンパク質の断片ペプチド(1-44)5μg/300μl、及びPBS 300μl(陰性コントロール群)の5回投与を行った。過剰量のケタミンおよびキシラジンを投与して安楽死させた後に心臓を採取した。OTCコンパウンドに組織を包埋し厚さ5 μmの凍結切片を作成した。抗マウスPDGFRα抗体を用い次のように免疫組織を行った。1次抗体はPDGFRα Rabbit anti-PDGF receptor alpha antibody (Abcam社製 AB 61219)を使用した。2次抗体はAlexa 555 goat anti-rabbit antibody(Molecular Probes)、核染色は4,6-diamino-2-phenylinodole(DAPI, Molecular Probes)を使用した。撮影には共焦点レーザー顕微鏡(FV300, オリンパス社製)を使用した。組織に集積した骨髄由来間葉系幹細胞の数については、ランダムに選択した5つの切片の全領域に存在するGFPとPDGFRα両方が陽性細胞の数を計測し平均値を算定した。また、RNeasy Kit (Qiagen社製)を用いて心筋組織からRNAを抽出し、Omniscript Reverse Transcriptase (Qiagen 社製)を用いて逆転写反応を行い、cDNAを得た。Gene Amp(R)PCR System 9700 (Life Technologies Japan 社製)を使用して前述のcDNAを鋳型としたリアルタイムPCRを行い、TNFα及びIL-1βのmRNA量をGAPDHのmRNA量との比として定量した。心機能の改善評価は、Vivid 7 echocardiography system と12-MHZ transducer (General Electric 社製)を使用してLVDd(Dd:左室拡張末期径)、LVDs(Ds:左室収縮末期径)、LVEF(EF:左室駆出率)を計測することによって行った。
Claims (3)
- HMGB1断片ペプチドを含有する、心筋梗塞を治療するために用いられる医薬組成物。
- 前記HMGB1断片ペプチドが、配列番号:3に示されるアミノ酸配列を含むペプチドである、請求項1に記載の医薬組成物。
- 前記HMGB1断片ペプチドが、配列番号:3に示されるアミノ酸配列からなるペプチドである、請求項1に記載の医薬組成物。
Applications Claiming Priority (3)
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JP2012235785 | 2012-10-25 | ||
JP2012235785 | 2012-10-25 | ||
PCT/JP2013/078758 WO2014065347A1 (ja) | 2012-10-25 | 2013-10-24 | Hmgb1断片を利用した新規心筋梗塞の治療法 |
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US (1) | US9623078B2 (ja) |
EP (1) | EP2913058B1 (ja) |
JP (1) | JP6253589B2 (ja) |
KR (1) | KR102146815B1 (ja) |
CN (1) | CN104884076B (ja) |
AU (1) | AU2013335684B2 (ja) |
BR (1) | BR112015009037A2 (ja) |
CA (1) | CA2889275C (ja) |
DK (1) | DK2913058T3 (ja) |
ES (1) | ES2660420T3 (ja) |
HK (2) | HK1211488A1 (ja) |
MX (1) | MX361259B (ja) |
PL (1) | PL2913058T3 (ja) |
RU (1) | RU2647467C2 (ja) |
SG (1) | SG11201503236RA (ja) |
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EP2913058B1 (en) | 2017-12-20 |
MX361259B (es) | 2018-11-30 |
KR20150103660A (ko) | 2015-09-11 |
DK2913058T3 (en) | 2018-02-19 |
HK1212887A1 (zh) | 2016-06-24 |
AU2013335684A1 (en) | 2015-05-14 |
EP2913058A4 (en) | 2016-04-13 |
RU2015119517A (ru) | 2016-12-20 |
CN104884076A (zh) | 2015-09-02 |
SG11201503236RA (en) | 2015-06-29 |
CA2889275C (en) | 2021-06-15 |
TR201802122T4 (tr) | 2018-03-21 |
MX2015005252A (es) | 2015-10-29 |
US20150273017A1 (en) | 2015-10-01 |
EP2913058A1 (en) | 2015-09-02 |
PL2913058T3 (pl) | 2018-04-30 |
RU2647467C2 (ru) | 2018-03-15 |
US9623078B2 (en) | 2017-04-18 |
ES2660420T3 (es) | 2018-03-22 |
WO2014065347A1 (ja) | 2014-05-01 |
CA2889275A1 (en) | 2014-05-01 |
BR112015009037A2 (pt) | 2017-11-14 |
CN104884076B (zh) | 2017-10-03 |
AU2013335684B2 (en) | 2017-06-29 |
HK1211488A1 (en) | 2016-05-27 |
KR102146815B1 (ko) | 2020-08-21 |
JP6253589B2 (ja) | 2017-12-27 |
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