Blood:功能异常的FIX可干扰正常的FIX发挥止血作用

2019-04-18 MedSci MedSci原创

IX因子(FIX)可与内皮细胞下基底膜的胶原IV (Col4)结合。在B型血友病中,FIX-Col4的结合可减少输注的FIX的血浆回收率,在止血过程中具有重要意义。在交联反应阴性(cross-reactive material negative, CRM-)的B型血友病小鼠模型中评估输注的BeneFix(FIXWT)的回收情况的研究表明Col4结合FIX的适合浓度为~405 nM(95% CI 3

IX因子(FIX)可与内皮细胞下基底膜的胶原IV (Col4)结合。在B型血友病中,FIX-Col4的结合可减少输注的FIX的血浆回收率,在止血过程中具有重要意义。

在交联反应阴性(cross-reactive material negative, CRM-)的B型血友病小鼠模型中评估输注的BeneFix(FIXWT)的回收情况的研究表明Col4结合FIX的适合浓度为~405 nM(95% CI 374-436 nM)。因此,与Col4结合的FIX量(血管储存量)是血浆FIX水平的几倍。

预防疗法的小鼠模型(输注150 IU/kg FIX后7天,检测隐静脉出血后的止血情况)中,FIXWT和半衰期延长的FIXs Alprolix(FIXFC)和Idelvion(FIXAIb)在CRM-小鼠中可产生相似的止血效果。

在流血的CRM- B型血友病小鼠中,输注FIX药物后,隐静脉受损部位形成第一个血栓的时间有明显差异:FIXWT &It; FIXFC &It; FIX AIb。但在大部分B型血友病(CRM+)患者的血液循环中都存在功能异常的FIX。在预防疗法的小鼠模型中 ,FIX的所有制剂都不能改善表达功能异常的FIX(FIXR333Q)的CRM+小鼠的止血作用;FIXR333Q可与功能正常的FIX竞争性结合Col4,FIX可能还通过其他通路发挥作用。

总而言之,CRM+ B型血友病小鼠模型提示内源性表达的功能异常的FIX可干扰FIX预防疗法的止血反应。

原始出处:

Brian Cooley, et al.Dysfunctional Endogenous FIX Impairs Prophylaxis in a Mouse Hemophilia B Model.Blood 2019 :blood.2018884015; doi: https://doi.org/10.1182/blood.2018884015 

本文系梅斯医学(MedSci)原创编译,转载需授权!

版权声明:
本网站所有内容来源注明为“梅斯医学”或“MedSci原创”的文字、图片和音视频资料,版权均属于梅斯医学所有。非经授权,任何媒体、网站或个人不得转载,授权转载时须注明来源为“梅斯医学”。其它来源的文章系转载文章,或“梅斯号”自媒体发布的文章,仅系出于传递更多信息之目的,本站仅负责审核内容合规,其内容不代表本站立场,本站不负责内容的准确性和版权。如果存在侵权、或不希望被转载的媒体或个人可与我们联系,我们将立即进行删除处理。
在此留言
评论区 (3)
#插入话题
  1. [GetPortalCommentsPageByObjectIdResponse(id=1914366, encodeId=c534191436646, content=<a href='/topic/show?id=7c90328e6f1' target=_blank style='color:#2F92EE;'>#功能异常#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=32876, encryptionId=7c90328e6f1, topicName=功能异常)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Tue May 14 14:39:00 CST 2019, time=2019-05-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1263068, encodeId=e924126306894, content=<a href='/topic/show?id=ebb5631e076' target=_blank style='color:#2F92EE;'>#止血#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=63170, encryptionId=ebb5631e076, topicName=止血)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6f7770, createdName=jeanqiuqiu, createdTime=Sat Apr 20 06:39:00 CST 2019, time=2019-04-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1575329, encodeId=97cd15e5329d8, content=<a href='/topic/show?id=b7a2e476fe' target=_blank style='color:#2F92EE;'>#FIX#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=7476, encryptionId=b7a2e476fe, topicName=FIX)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9c7b16091019, createdName=fengting8, createdTime=Sat Apr 20 06:39:00 CST 2019, time=2019-04-20, status=1, ipAttribution=)]
  2. [GetPortalCommentsPageByObjectIdResponse(id=1914366, encodeId=c534191436646, content=<a href='/topic/show?id=7c90328e6f1' target=_blank style='color:#2F92EE;'>#功能异常#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=32876, encryptionId=7c90328e6f1, topicName=功能异常)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Tue May 14 14:39:00 CST 2019, time=2019-05-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1263068, encodeId=e924126306894, content=<a href='/topic/show?id=ebb5631e076' target=_blank style='color:#2F92EE;'>#止血#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=63170, encryptionId=ebb5631e076, topicName=止血)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6f7770, createdName=jeanqiuqiu, createdTime=Sat Apr 20 06:39:00 CST 2019, time=2019-04-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1575329, encodeId=97cd15e5329d8, content=<a href='/topic/show?id=b7a2e476fe' target=_blank style='color:#2F92EE;'>#FIX#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=7476, encryptionId=b7a2e476fe, topicName=FIX)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9c7b16091019, createdName=fengting8, createdTime=Sat Apr 20 06:39:00 CST 2019, time=2019-04-20, status=1, ipAttribution=)]
    2019-04-20 jeanqiuqiu
  3. [GetPortalCommentsPageByObjectIdResponse(id=1914366, encodeId=c534191436646, content=<a href='/topic/show?id=7c90328e6f1' target=_blank style='color:#2F92EE;'>#功能异常#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=32876, encryptionId=7c90328e6f1, topicName=功能异常)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Tue May 14 14:39:00 CST 2019, time=2019-05-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1263068, encodeId=e924126306894, content=<a href='/topic/show?id=ebb5631e076' target=_blank style='color:#2F92EE;'>#止血#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=63170, encryptionId=ebb5631e076, topicName=止血)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6f7770, createdName=jeanqiuqiu, createdTime=Sat Apr 20 06:39:00 CST 2019, time=2019-04-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1575329, encodeId=97cd15e5329d8, content=<a href='/topic/show?id=b7a2e476fe' target=_blank style='color:#2F92EE;'>#FIX#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=7476, encryptionId=b7a2e476fe, topicName=FIX)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9c7b16091019, createdName=fengting8, createdTime=Sat Apr 20 06:39:00 CST 2019, time=2019-04-20, status=1, ipAttribution=)]
    2019-04-20 fengting8

相关资讯

Blood:CRISPR/Cas9成功恢复FIX敲除小鼠的FIX表达

很多遗传病,包括血友病,需要长期治疗。虽然肝靶向腺病毒(AAV)相关的基因疗法在治疗血友病的临床试验中取得了初步的成功,但尚未观察到长期、持续的治疗效果。现有研究人员对采用CRISPR/Case9介导的基因靶向疗法治疗B型血友病的效果进行研究。

Blood:基因疗法可显着降低B型血友病患者自发性出血概率。

血友病B基因疗法旨在改变患者的出血风险,并通过单一治疗提高内源性因子IX(FIX)的活性/合成,从而消除对FIX聚集的需求。AMT-060是由一种腺病毒相关病毒-5(AAV5)载体与驱动密码子最优化的野生型人类FIX基因的表达的肝特异性启动子相结合而成。研究人员招募了10位有严重的出血表现的B型血友病成年患者(FIX≤正常值的2%)进行一多国家的开放性研究。所有受试者检测AAV5中和抗体阴性。10