淀粉样假说之外,还有哪些阿兹海默病疗法值得关注?

2017-10-07 佚名 药明德康

阿兹海默病的新药研发是一片凶险的领域。据估计,这一领域内的新药研发失败率为99%,甚至高于癌症新药的失败率。其背后的原因之一,在于我们还没有完全理解这种疾病。神经科学领域有一项旷日持久的争论:一方面,科学家们相信靶向淀粉样蛋白依旧是治疗阿兹海默病的最佳方式;另一方面,近期挫折不断的临床研发则让怀疑主义者心生将“淀粉样蛋白假说”束之高阁的念头。

阿兹海默病的新药研发是一片凶险的领域。据估计,这一领域内的新药研发失败率为99%,甚至高于癌症新药的失败率。其背后的原因之一,在于我们还没有完全理解这种疾病。神经科学领域有一项旷日持久的争论:一方面,科学家们相信靶向淀粉样蛋白依旧是治疗阿兹海默病的最佳方式;另一方面,近期挫折不断的临床研发则让怀疑主义者心生将“淀粉样蛋白假说”束之高阁的念头。

对于新药研发人员来说,无论“淀粉样蛋白假说”是否是真理,能够跳出思维局限找到全新的治疗思路,对阿兹海默病的研发总能带来裨益。在今日的这篇文章中,我们也将与各位读者一道分析治疗阿兹海默病的三个新研发新思路。

免疫系统

阿兹海默病的一大特点是记忆的逐渐丧失。尽管这一症状出现在神经系统,越来越多的证据却表明,身体的免疫系统在潜移默化中,也会对此造成影响。因此,科学家们正在寻找调控免疫系统的方法,防止它错误地攻击大脑。

这里面的关键是小胶质细胞(microglia)。它是中枢神经系统里的“免疫步兵”,负责清理能传染疾病的入侵者,以及不被需要的细胞。当它被激活时,就会带来组织炎症,而这一炎症反应可能会诱发阿兹海默病的进展。

“在阿兹海默病患者中,我们能明显看到炎性变化,”德州大学圣安东尼奥大学(University of Texas at San Antonio)的神经科学教授George Perry说道:“炎症是衰老的关键,在整个过程中悄悄扮演了重要角色。”

这一点已经成为了目前的共识,但说起来容易做起来难。如何针对中枢神经系统内的炎症,是一个挑战。目前,两家生物技术公司Annexon Biosciences与Alector正在探索一种叫做C1q的蛋白的潜力。去年,发表在《科学》上的一项研究表明,这种蛋白在经典的补体通路中扮演了重要角色。当它在突触内聚集时,就像是竖起了“来攻击我”的旗帜,这些突触也会被免疫细胞所攻击,带来潜在的记忆丧失与大脑萎缩。在动物实验里,抑制C1q蛋白能有效让健康突触免受免疫系统的攻击。这两家公司也期望将这一重要发现应用于人体。

由克利夫兰诊所(Cleveland Clinic)独立出的NeuroTherapia也希望能缓解大脑中的炎症反应。他们的在研新药NTRX-07能靶向脑中的大麻素受体,让过度活跃的小胶质细胞平静下来。按计划,它将在一年内把新药推进到人体临床试验阶段。

西奈山伊坎医学院(Icahn School of Medicine at Mount Sinai)的Alison Goate教授则将目光放在了炎症反应的上游。她分离出了一些可以控制小胶质细胞行为的基因:一种叫做TREM2的基因有望能保护大脑组织免于小胶质细胞的无端攻击,另一种叫做PU.1的基因则有相反的作用。“我们正在研究这些影响阿兹海默病风险的基因之间如何相互关联,在细胞内形成一个网络,” Goate教授说:“目前的关键是,这张网络中,哪些节点是好的成药靶点?”尽管目前还为时过早,但将来,或许会有针对TREM2与PU.1的新药问世。

表观遗传学

表观遗传学是相对较新的领域。通过研究基因表达的调控,我们能更好地理解生物的运作机理。研究人员也期待,我们能借由表观遗传学,了解大脑组织为何会不合时宜地发生死亡。

其中一个富有潜力的靶点是HDAC2这是一种酶,能够调控一些关键基因的表达,而这些基因会影响新突触的诞生。如果HDAC2蛋白过多,就会影响到大脑的自我修复能力。而抑制这个酶,在动物模型中展现出了令人欣喜的脑功能改善。位于麻省的生物技术初创公司Rodin Therapeutics正在开发安全的HDAC2抑制剂。如果一切顺利,这些新药有望穿透血脑屏障,在人体中重复小鼠体内看到的积极现象。

“如果我们减少HDAC2的表达,就能重新激活关键基因,恢复记忆。” 位于麻省理工学院的蔡立慧教授说道。这名华人学者在HDAC2与阿兹海默病的关联上做出了许多先驱性的工作。目前,她的团队正在考量另一种不同的策略。不久前,她的团队发现一种叫做Sp3的蛋白能结合大脑中的HDAC2,共同调节神经中的基因表达。当Sp3的水平被敲低后,小鼠大脑中的突触有了重生的迹象。

位于西班牙的Oryzon Genomics则已经进入了人体试验阶段。他们的在研新药ORY-2001能靶向LSD1与MAOB,从而促进那些有利于突触形成的基因表达。在健康的志愿者中,这款新药的安全性已经得到了验证。明年,他们计划在阿兹海默病患者中开始试验。“这个项目在治疗阿兹海默病的表观遗传学疗法中处于领先地位,” 阿兹海默病新药发现基金会(Alzheimer’s Drug Discovery Foundation)的首席科学官Howard Fillit博士说道:“我们对这项研究感到非常兴奋!”

药物之外

阿兹海默病的新药研发历史实在不容乐观。为了尽快给患者们带来有效的疗法,或许我们可以考虑其他方案。目前,一些证据表明特殊波长的光可以改善症状。德州大学(University of Texas)的研究人员们正在开发这种光疗法。按他们的设想,这种光疗法能激活调控氧气消耗的酶,从而让脑细胞获得能量,提高认知能力。今年4月,一项研究表明,每周接受一次光疗,能提高健康志愿者的反应能力与记忆。接下来,这些科学家想要在阿兹海默病老年患者中测试这一概念,了解光疗能否延缓神经退化。

蔡立慧教授同样在考虑光疗。与德州大学的策略不一样,他们使用光遗传学的技术,先在小鼠脑中植入改造的神经元,再植入特殊的光纤维。在特定波长的光照下,小鼠的记忆力和学习能力得到了改善。当然,在大脑中植入光纤维的方法具有侵入性,因此蔡立慧教授的团队进一步对这项技术做了改进,在减少操作风险的同时,还能带来类似的益处。目前,一家名为Cognito Therapeutics的公司得到了这项技术的许可,进行医疗设备的开发。

在这些充满希望的疗法浮出水面之际,我们也需要记住这样一个事实:阿兹海默病的新药在动物实验中从来不缺惊喜,但这种惊喜往往不能在人体中重复。其中的一个原因在于,自然环境中的小鼠很少会自发出现这种疾病,因此动物模型能带给我们多少洞见,依然是件存疑的事。但不管怎样,没有尝试,就没有新疗法的问世。我们期待在这一领域能尽早出现研发英雄,造福患者!

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    2017-10-08 大叔默默路过

    其实.应该说炎症加速了细胞的衰变过程.也间接加速了新生细胞的更新.只是更新速度不如衰老速度快罢了

    0

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    2017-10-08 sunfeifeiyang

    学习

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1735477, encodeId=02b41e354773c, content=<a href='/topic/show?id=7f019e71750' target=_blank style='color:#2F92EE;'>#阿兹海默病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97717, encryptionId=7f019e71750, topicName=阿兹海默病)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9ff833907849, createdName=xre2019, createdTime=Wed Jul 04 17:25:00 CST 2018, time=2018-07-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251299, encodeId=ae17251299a9, content=其实.应该说炎症加速了细胞的衰变过程.也间接加速了新生细胞的更新.只是更新速度不如衰老速度快罢了, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210427/b594a756d77e4171b5313e531ef89b43/31c000a8a97d4872b698c80fb8a33369.jpg, createdBy=624b2152505, createdName=大叔默默路过, createdTime=Sun Oct 08 08:51:02 CST 2017, time=2017-10-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251235, encodeId=6dc7251235a2, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/09/07/a9772c74ffd6edc03a7f9af07b4747f6.jpg, createdBy=b3722138742, createdName=sunfeifeiyang, createdTime=Sun Oct 08 00:58:33 CST 2017, time=2017-10-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251192, encodeId=bedf251192e5, content=学习了受益匪浅, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/ajNVdqHZLLDicHg2ldsSNmib46PmdzpO7CQEmPjuULp1v45zPWwMYhrnXgvl3OtmUCZSQfgITWn96X9moL94nUGA/0, createdBy=28072041016, createdName=131****1460, createdTime=Sat Oct 07 20:27:05 CST 2017, time=2017-10-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251183, encodeId=cc8b2511838a, content=学习了.谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mONcle9pic3zSn0GqHrsfLGSUSR8zwnWWLT4FMl5XH8S58HuZslVkLsAPbXDXaliagK7TOxQfmngKibG1yrDonepCLDkcxGk8hS/0, createdBy=b8282062892, createdName=changjiu, createdTime=Sat Oct 07 19:56:08 CST 2017, time=2017-10-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251163, encodeId=ed6425116362, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfBfgWn9nXBgH1sNSiaOAKhsKpN40jDHQKqcRzovau5VibLvREN8uxnu9sKoScBicHSiaDMmbveibFdrBiaD4k4IOPwlG/0, createdBy=b5d11730951, createdName=Jackie Li, createdTime=Sat Oct 07 17:48:30 CST 2017, time=2017-10-07, status=1, ipAttribution=)]
    2017-10-07 131****1460

    学习了受益匪浅

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=1735477, encodeId=02b41e354773c, content=<a href='/topic/show?id=7f019e71750' target=_blank style='color:#2F92EE;'>#阿兹海默病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97717, encryptionId=7f019e71750, topicName=阿兹海默病)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9ff833907849, createdName=xre2019, createdTime=Wed Jul 04 17:25:00 CST 2018, time=2018-07-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251299, encodeId=ae17251299a9, content=其实.应该说炎症加速了细胞的衰变过程.也间接加速了新生细胞的更新.只是更新速度不如衰老速度快罢了, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210427/b594a756d77e4171b5313e531ef89b43/31c000a8a97d4872b698c80fb8a33369.jpg, createdBy=624b2152505, createdName=大叔默默路过, createdTime=Sun Oct 08 08:51:02 CST 2017, time=2017-10-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251235, encodeId=6dc7251235a2, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/09/07/a9772c74ffd6edc03a7f9af07b4747f6.jpg, createdBy=b3722138742, createdName=sunfeifeiyang, createdTime=Sun Oct 08 00:58:33 CST 2017, time=2017-10-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251192, encodeId=bedf251192e5, content=学习了受益匪浅, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/ajNVdqHZLLDicHg2ldsSNmib46PmdzpO7CQEmPjuULp1v45zPWwMYhrnXgvl3OtmUCZSQfgITWn96X9moL94nUGA/0, createdBy=28072041016, createdName=131****1460, createdTime=Sat Oct 07 20:27:05 CST 2017, time=2017-10-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251183, encodeId=cc8b2511838a, content=学习了.谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mONcle9pic3zSn0GqHrsfLGSUSR8zwnWWLT4FMl5XH8S58HuZslVkLsAPbXDXaliagK7TOxQfmngKibG1yrDonepCLDkcxGk8hS/0, createdBy=b8282062892, createdName=changjiu, createdTime=Sat Oct 07 19:56:08 CST 2017, time=2017-10-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251163, encodeId=ed6425116362, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfBfgWn9nXBgH1sNSiaOAKhsKpN40jDHQKqcRzovau5VibLvREN8uxnu9sKoScBicHSiaDMmbveibFdrBiaD4k4IOPwlG/0, createdBy=b5d11730951, createdName=Jackie Li, createdTime=Sat Oct 07 17:48:30 CST 2017, time=2017-10-07, status=1, ipAttribution=)]
    2017-10-07 changjiu

    学习了.谢谢

    0

  6. [GetPortalCommentsPageByObjectIdResponse(id=1735477, encodeId=02b41e354773c, content=<a href='/topic/show?id=7f019e71750' target=_blank style='color:#2F92EE;'>#阿兹海默病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97717, encryptionId=7f019e71750, topicName=阿兹海默病)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9ff833907849, createdName=xre2019, createdTime=Wed Jul 04 17:25:00 CST 2018, time=2018-07-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251299, encodeId=ae17251299a9, content=其实.应该说炎症加速了细胞的衰变过程.也间接加速了新生细胞的更新.只是更新速度不如衰老速度快罢了, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210427/b594a756d77e4171b5313e531ef89b43/31c000a8a97d4872b698c80fb8a33369.jpg, createdBy=624b2152505, createdName=大叔默默路过, createdTime=Sun Oct 08 08:51:02 CST 2017, time=2017-10-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251235, encodeId=6dc7251235a2, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/09/07/a9772c74ffd6edc03a7f9af07b4747f6.jpg, createdBy=b3722138742, createdName=sunfeifeiyang, createdTime=Sun Oct 08 00:58:33 CST 2017, time=2017-10-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251192, encodeId=bedf251192e5, content=学习了受益匪浅, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/ajNVdqHZLLDicHg2ldsSNmib46PmdzpO7CQEmPjuULp1v45zPWwMYhrnXgvl3OtmUCZSQfgITWn96X9moL94nUGA/0, createdBy=28072041016, createdName=131****1460, createdTime=Sat Oct 07 20:27:05 CST 2017, time=2017-10-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251183, encodeId=cc8b2511838a, content=学习了.谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mONcle9pic3zSn0GqHrsfLGSUSR8zwnWWLT4FMl5XH8S58HuZslVkLsAPbXDXaliagK7TOxQfmngKibG1yrDonepCLDkcxGk8hS/0, createdBy=b8282062892, createdName=changjiu, createdTime=Sat Oct 07 19:56:08 CST 2017, time=2017-10-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=251163, encodeId=ed6425116362, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfBfgWn9nXBgH1sNSiaOAKhsKpN40jDHQKqcRzovau5VibLvREN8uxnu9sKoScBicHSiaDMmbveibFdrBiaD4k4IOPwlG/0, createdBy=b5d11730951, createdName=Jackie Li, createdTime=Sat Oct 07 17:48:30 CST 2017, time=2017-10-07, status=1, ipAttribution=)]
    2017-10-07 Jackie Li

    学习

    0

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