JP2005514442A - 神経細胞の再生におけるil6r/il6キメラの使用 - Google Patents
神経細胞の再生におけるil6r/il6キメラの使用 Download PDFInfo
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Abstract
Description
IL6RIL6キメラの効果を胚発生の14日目にDRGに存在するの発達中の神経グリア細胞に対して調べた。DRG細胞は、ルイスラットE14胚から前述したように調製した(Kleitman et. 1991 and Haggiag et al, 1999)。分離したDRG細胞をまず4日間、カバーグラス(glass coverslips)(フィブロネクチン−コート)上で、1% ニワトリ胚抽出液、bFGF 20ng/ml、1% N2補助剤(ギブコ)、2% B27補助剤(ギブコ)、50μM メルカプトエタノール、35mg/ml(110nM) レチノイン酸を含むDMEM/F12(1:1)からなる培地で培養した(Morrison et al, 1997)。この時点で、いくつかの培養物を固定し(4日)、そして他のものには精製rhIL6R/IL6キメラ(Chebath et al. 1997に記載されたようにCHO細胞で産生)を補足し200ng/mlすなわち2.3nMで添加した。他の培養物は、添加なし(NT)か、または2nM 骨形成タンパク質−2(BMP−2)と共に培養を続けた。9日後(培養開始から13日目)、DRG細胞を固定し、ニューロン特異的ベータIIIチューブリンマーカーについての蛍光免疫染色に付し、UV光下で顕微鏡で撮影した。図1には、添加なし、すなわちNTの培養物(上段左)にはほとんど未発達細胞が示されておらず、一方IL6RIL6を含んでいる培養物(上段中央および下段右)には、多くの神経体(neuroal bodies)が発達した軸索網と共に見られた。特に興味深いのは、増殖し、軸索の発達である原始ニューロンの存在(下段左)である。BMP−2を投与された培養物(上段右)は、NT培養物と同じであった。4日で固定された培養物には、目視できるニューロンが存在しない。これは、IL6RIL6がニューロンの新規の分化を誘発するということを証明している。
実施例1に記載したように調製したDRG細胞培養物は、とりわけニューロン、グリア細胞および筋線維芽細胞などの種々の細胞系統の前駆細胞として知られる神経堤細胞からなる不均一の細胞集団で構成される。神経堤細胞は、外胚葉においてはメラノサイトのもとにもなる。IL6RIL6キメラは、未分化の神経堤前駆細胞の豊富なサブ集団において、その分子がこれらの前駆細胞を成熟ニューロンへ分化させるかどうか調べるためにテストされた。そのような神経堤前駆細胞の豊富なサブ集団は、LNGFR陽性細胞に対するラット胚E14DRG細胞の蛍光発色セルソーター(FACS)により単離した。このp75低親和性NGF受容体は、神経堤細胞および初期神経グリア前駆細胞の特異的マーカーであり、NGF受容体というよりむしろニューロトロフィン受容体である(実際、ニューロンが分化すると、それらはp75LNGFRを失い、そして機能的なNGF受容体であるTrkAを獲得する。)。つぎに、LNGFR+−ソート細胞をカバーガラス上で実施例1に記載したように培養した。ある培養物には200ng/mlのIL6RIL6を補足し、他のものは処理しないでおいた。12日後、固定した細胞をニューロン特異的ベータIIIチューブリンに対して蛍光免疫染色に付した。図3は、IL6RIL6で処理した神経堤細胞前駆体の豊富な集団は分化し、密集した神経網を形成することを示す。多くのニューロン細胞体から軸索の密集した流れが発達しているのが見られた。一方、サイトカイン非存在下では、不完全に発達したニューロンがほんのわずか観察された。これは、BMP−2での培養物においても観察され(示さない)、IL6RIL6処理培養物における強い神経発達と対照的である。
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Claims (71)
- 中枢神経系(CNS)での神経細胞再生の誘導のための医薬の製造における、IL6R/IL6キメラ、そのムテイン、融合タンパク質、機能的誘導体、活性画分、循環置換誘導体または塩の使用。
- 医薬がさらに胚由来の神経前駆細胞を含有する請求項1記載の使用。
- 医薬がさらに成体由来の神経前駆細胞を含有する請求項1記載の使用。
- 医薬がさらに新生児由来の神経前駆細胞を含有する請求項1記載の使用。
- 医薬がさらにグリア細胞を含有する請求項1、2、3または4記載の使用。
- 医薬がさらに、NGF、NTFs、BDNF、IGFs、FGFs、CNTF、LIF、G−CSF、OSM、IL−11、BMP−2、GGF−2、Nrg1およびTGFから選択される神経栄養因子および/またはサイトカインを含有する請求項1、2、3、4または5記載の使用。
- CNSでの神経細胞再生の誘導のための医薬の製造における、IL6R/IL6キメラ、そのムテイン、融合タンパク質または活性画分のコード配列を含有する発現ベクターの使用。
- ベクターがレンチウイルスベクターである請求項7記載の使用。
- 医薬がさらに胚由来の神経前駆細胞を含有する請求項7または8記載の使用。
- 医薬がさらに成体由来の神経前駆細胞を含有する請求項7または8記載の使用。
- 医薬がさらに新生児由来の神経前駆細胞を含有する請求項7または8記載の使用。
- 医薬がさらにグリア細胞を含有する請求項7、8、9、10または11記載の使用。
- 医薬がさらに、NGF、NTFs、BDNF、IGFs、FGFs、CNTF、LIF、G−CSF、OSM、IL−11、BMP−2、GGF−2、Nrg1およびTGFから選択される神経栄養因子および/またはサイトカインを含有する請求項7、8、9、10、11または12記載の使用。
- CNSでの神経細胞再生の誘導のための医薬の製造における、組換えIL6R/IL6キメラ、またはそのムテイン、融合タンパク質もしくは活性画分を発現する細胞の使用。
- 医薬がさらに胚由来の神経前駆細胞を含有する請求項14記載の使用。
- 医薬がさらに成体由来の神経前駆細胞を含有する請求項14記載の使用。
- 医薬がさらに新生児由来の神経前駆細胞を含有する請求項14記載の使用。
- 医薬がさらにグリア細胞を含有する請求項14、15、16または17記載の使用。
- 医薬がさらに、NGF、NTFs、BDNF、IGFs、FGFs、CNTF、LIF、G−CSF、OSM、IL−11、BMP−2、GGF−2、Nrg1およびTGFから選択される神経栄養因子および/またはサイトカインを含有する請求項14、15、16、17または18記載の使用。
- CNSでの神経細胞再生の誘導のための医薬の製造における、IL6R/IL6キメラ、またはそのムテイン、融合タンパク質、活性画分、循環置換誘導体もしくは塩により事前に刺激される神経前駆細胞の使用。
- 神経前駆細胞が胚由来である請求項20記載の使用。
- 神経前駆細胞が成体由来である請求項20記載の使用。
- 神経前駆細胞が新生児由来である請求項20記載の使用。
- 医薬がさらにグリア細胞を含有する請求項20、21、22または23記載の使用。
- 医薬がさらに、NGF、NTFs、BDNF、IGFs、FGFs、CNTF、LIF、G−CSF、OSM、IL−11、BMP−2、GGF−2、Nrg1およびTGFから選択される神経栄養因子および/またはサイトカインを含有する請求項20、21、22、23または24記載の使用。
- 損傷した中枢神経系(CNS)での神経細胞の再生方法であって、治療に有効量のIL6R/IL6キメラ、またはそのムテイン、融合タンパク質、機能的誘導体、活性画分、循環置換誘導体もしくは塩を、必要とする患者に投与することからなる方法。
- さらに胚幹細胞の投与を含む請求項26項記載の方法。
- さらに神経前駆細胞の投与を含む請求項26項記載の方法。
- 前駆細胞が胚由来である請求項28項記載の方法。
- 前駆細胞が成体由来である請求項28項記載の方法。
- 前駆細胞が新生児由来である請求項28項記載の方法。
- さらにグリア細胞の投与を含む請求項26、27、28、29、30または31項記載の方法。
- 細胞がIL6R/IL6キメラで事前に刺激されている請求項27、28、29、30、31または32記載の方法。
- さらに、NGF、NTFs、BDNF、IGFs、FGFs、CNTF、LIF、G−CSF、OSM、IL−11、BMP−2、GGF−2、Nrg1およびTGFから選択される神経栄養因子および/またはサイトカインの投与を含有する請求項26、27、28、29、30、31、32または33記載の方法。
- 神経性疾患を患う患者における損傷した中枢神経系(CNS)の神経細胞の再生のための請求項26、27、28、29、30、31、32、33または34記載の方法。
- 神経性疾患がアルツハイマー病、パーキンソン病、多発性硬化症およびハンチントン舞踏病から選択される請求項35記載の方法。
- 神経性疾患が脳卒中、酸素欠乏症/窒息、身体的損傷、毒への暴露および悪性疾患により引き起こされる請求項35記載の方法。
- 損傷した中枢神経系(CNS)での神経細胞の再生方法であって、IL−6R/Il−6キメラ、またはそのムテイン、融合タンパク質もしくは活性画分のコード配列を含有する発現ベクターを、必要とする患者に投与することを含む方法。
- さらに胚幹細胞の投与を含む請求項38項記載の方法。
- さらに神経前駆細胞の投与を含む請求項38項記載の方法。
- 細胞が胚由来である請求項40項記載の方法。
- 細胞が成体由来である請求項40項記載の方法。
- 細胞が新生児由来である請求項40項記載の方法。
- さらにグリア細胞の投与を含む請求項38、39、40、41、42または43項記載の方法。
- 細胞がIL6R/IL6キメラで事前に刺激されている請求項39、40、41、42、43または44記載の方法。
- さらに、NGF、NTFs、BDNF、IGFs、FGFs、CNTF、LIF、G−CSF、OSM、IL−11、BMP−2、GGF−2、Nrg1およびTGFから選択される神経栄養因子および/またはサイトカインの投与を含有する請求項38、39、40、41、42、43、44または45記載の方法。
- 神経性疾患を患う患者において損傷した中枢神経系(CNS)の神経細胞を回復させるための請求項38、39、40、41、42、43、44、45または46記載の方法。
- 神経性疾患がアルツハイマー病、パーキンソン病、多発性硬化症およびハンチントン舞踏病から選択される請求項47記載の方法。
- 神経性疾患が脳卒中、酸素欠乏症/窒息、身体的損傷、毒への暴露および悪性疾患により引き起こされる請求項47記載の方法。
- 治療に有効量のIL6R/IL6キメラ、そのムテイン、融合タンパク質、機能的誘導体、活性画分、循環置換誘導体または塩を、必要とする対象に投与することを含む再生方法。
- さらに胚幹細胞の投与を含む請求項50項記載の方法。
- さらに神経前駆細胞の投与を含む請求項50項記載の方法。
- 前駆細胞が胚由来である請求項52項記載の方法。
- 前駆細胞が成体由来である請求項52項記載の方法。
- 前駆細胞が新生児由来である請求項52項記載の方法。
- さらにグリア細胞の投与を含む請求項50、51、52、53、54または55項記載の方法。
- 細胞がIL6R/IL6キメラで事前に刺激されている請求項51、52、53、54、55または56記載の方法。
- さらに、NGF、NTFs、BDNF、IGFs、FGFs、CNTF、LIF、G−CSF、OSM、IL−11、BMP−2、GGF−2、Nrg1およびTGFから選択される神経栄養因子および/またはサイトカインの投与を含有する請求項50、51、52、53、54、55、56または57記載の方法。
- 損傷した中枢神経系(CNS)での神経再生方法であって、神経前駆細胞をIL6R/IL6キメラ、そのムテイン、融合タンパク質、機能的誘導体、活性画分、循環置換誘導体または塩で刺激すること、およびその細胞を必要とする患者に移植することを含む方法。
- 移植前に生体外で神経前駆細胞がIL6R/IL6を含む組成物で刺激される請求項59記載の方法。
- 移植後に生体内で神経前駆細胞がIL6R/IL6を含む組成物で刺激されるかまたは移植中にIL6R/IL6を投与する請求項59記載の方法。
- 神経前駆細胞が、IL6R/IL6キメラを発現する組換え細胞と共に移植される請求項59記載の方法。
- 前駆細胞が胚由来である請求項59、60、61または62記載の方法。
- 前駆細胞が成体由来である請求項59、60、61または62記載の方法。
- 前駆細胞がグリア細胞と共に移植される請求項59、60、61または62記載の方法。
- 前駆細胞がNGF、NTFs、BDNF、IGFs、FGFs、CNTF、LIF、G−CSF、OSM、IL−11、BMP−2、GGF−2、Nrg1およびTGFから選択される神経栄養因子および/またはサイトカインと共移植される請求項59、60、61、62、63、64、65、66または67記載の方法。
- 患者がニューロンの喪失または萎縮を患う請求項59、60、61、62、63、64、65または66記載の方法。
- ニューロンの喪失または萎縮が加齢により引き起こされる請求項67記載の方法。
- ニューロンの喪失または萎縮が神経性疾患により引き起こされる請求項67記載の方法。
- 神経性疾患がアルツハイマー病、パーキンソン病、多発性硬化症およびハンチントン舞踏病から選択される請求項69記載の方法。
- ニューロンの喪失または萎縮が身体的損害により引き起こされる請求項67記載の方法。
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IL14741201A IL147412A0 (en) | 2001-12-31 | 2001-12-31 | The use of il6r/il6 chimera in nerve cell regeneration |
PCT/IL2002/001058 WO2003059376A1 (en) | 2001-12-31 | 2002-12-31 | The use of il6r/il6 chimera in nerve cell regeneration |
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EP (1) | EP1461066B1 (ja) |
JP (1) | JP4685354B2 (ja) |
AU (1) | AU2002361489B2 (ja) |
CA (1) | CA2472203C (ja) |
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JP2015525217A (ja) * | 2012-06-08 | 2015-09-03 | アルカーメス,インコーポレイテッド | アゴニストおよびアンタゴニストとしての循環置換により修飾されるリガンド |
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CA2527847C (en) * | 2003-06-12 | 2015-09-29 | Yeda Research & Development Co. Ltd | Enhancement of oligodendrocyte differentiation |
IL157309A0 (en) | 2003-08-07 | 2004-02-19 | Applied Research Systems | Method for the purification of a non-immunoglobulin protein |
CA2735272A1 (en) * | 2004-06-23 | 2006-01-05 | Tissuegene, Inc. | Nerve regeneration by transplanting cells expressing recombinant transforming growth factor superfamily protein |
US8476070B2 (en) * | 2005-08-29 | 2013-07-02 | Technion Research & Development Foundation Limited | Media for culturing stem cells |
GB0815216D0 (en) * | 2008-08-21 | 2008-09-24 | Asterion Ltd | Interleukin |
AU2010223268B2 (en) * | 2009-03-12 | 2015-04-23 | Haase Investments Gmbh | Bone morphogenetic protein 2 (BMP2 ) variants with reduced BMP antagonist sensitivity |
US20120219535A1 (en) * | 2009-10-02 | 2012-08-30 | University Of Southern California | Cranial neural crest stem cells and culture condition that supports their growth |
JP2013535507A (ja) * | 2010-08-13 | 2013-09-12 | ジョージタウン ユニバーシティ | Ggf2および使用方法 |
WO2020006469A1 (en) * | 2018-06-29 | 2020-01-02 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Methods for treating and reducing traumatic brain injury-associated impairments using sgp130 |
IL299911A (en) * | 2020-08-14 | 2023-03-01 | Kite Pharma Inc | Improving immune cell function |
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WO2000078331A2 (en) * | 1999-06-21 | 2000-12-28 | Yeda Research And Development Co. Ltd. | Il6ril6 chimera for the treatment of neurodegenerative diseases |
JP2001509371A (ja) * | 1997-07-10 | 2001-07-24 | イエダ リサーチ アンド ディベロップメント カンパニー リミテッド | キメラのインターロイキン−6可溶性受容体/リガンドタンパク質、その類似体およびその使用 |
WO2002022149A1 (en) * | 2000-09-14 | 2002-03-21 | Ares Trading S.A. | Use of il-6r/il-6 chimera in huntington's disease |
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US6749850B1 (en) * | 1999-08-18 | 2004-06-15 | The General Hospital Corporation | Methods, compositions and kits for promoting recovery from damage to the central nervous system |
WO2001076507A2 (en) * | 2000-04-11 | 2001-10-18 | The University Of Miami | Use of oxygen carriers to improve grafted cell survival in neural transplantation |
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JPH0987198A (ja) * | 1995-09-19 | 1997-03-31 | Tosoh Corp | 神経細胞伸長剤 |
JP2001509371A (ja) * | 1997-07-10 | 2001-07-24 | イエダ リサーチ アンド ディベロップメント カンパニー リミテッド | キメラのインターロイキン−6可溶性受容体/リガンドタンパク質、その類似体およびその使用 |
WO2000078331A2 (en) * | 1999-06-21 | 2000-12-28 | Yeda Research And Development Co. Ltd. | Il6ril6 chimera for the treatment of neurodegenerative diseases |
WO2002022149A1 (en) * | 2000-09-14 | 2002-03-21 | Ares Trading S.A. | Use of il-6r/il-6 chimera in huntington's disease |
Cited By (4)
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JP2015525217A (ja) * | 2012-06-08 | 2015-09-03 | アルカーメス,インコーポレイテッド | アゴニストおよびアンタゴニストとしての循環置換により修飾されるリガンド |
JP2018038389A (ja) * | 2012-06-08 | 2018-03-15 | アルカーメス,インコーポレイテッド | アゴニストおよびアンタゴニストとしての循環置換により修飾されるリガンド |
JP2019195332A (ja) * | 2012-06-08 | 2019-11-14 | アルカーメス ファーマ アイルランド リミテッド | アゴニストおよびアンタゴニストとしての循環置換により修飾されるリガンド |
JP7048543B2 (ja) | 2012-06-08 | 2022-04-05 | アルカーメス ファーマ アイルランド リミテッド | アゴニストおよびアンタゴニストとしての循環置換により修飾されるリガンド |
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US7824670B2 (en) | 2010-11-02 |
AU2002361489B2 (en) | 2008-05-08 |
IL162482A (en) | 2013-06-27 |
WO2003059376A1 (en) | 2003-07-24 |
JP4685354B2 (ja) | 2011-05-18 |
CA2472203C (en) | 2014-02-18 |
ES2535156T3 (es) | 2015-05-05 |
WO2003059376A8 (en) | 2003-10-09 |
CA2472203A1 (en) | 2003-07-24 |
US20050220761A1 (en) | 2005-10-06 |
EP1461066B1 (en) | 2015-02-25 |
AU2002361489A1 (en) | 2003-07-30 |
IL147412A0 (en) | 2002-08-14 |
EP1461066A1 (en) | 2004-09-29 |
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