Science Translational Medicine:帕金森病治疗的一大步:LRRK2抑制剂临床试验评估

2022-06-17 王聪 “生物世界”公众号

全世界有超过1000万人患有帕金森病,每年还有约60000名新患者确诊。患者大脑中产生多巴胺的神经元丧失,影响运动和认知,导致出现震颤、肌肉僵硬、意识模糊和痴呆等症状。

帕金森病(Parkinson’s Disease,PD),是一种复杂的神经退行性疾病,也是世界上第二常见的神经退行性疾病,仅次于阿尔茨海默病,影响着约1%-2%的65岁及以上老人。随着全球人口老龄化,帕金森病患病率将大幅增加。

目前,全世界有超过1000万人患有帕金森病,每年还有约60000名新患者确诊。患者大脑中产生多巴胺的神经元丧失,影响运动和认知,导致出现震颤、肌肉僵硬、意识模糊和痴呆等症状。

2022年6月8日,Denali Therapeutics 公司的研究人员在 Science 子刊 Science Translational Medicine 发表了题为:Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease 的研究论文。

这项临床前和临床研究表明,LRRK2 是帕金森病的一个有潜力的改善和治疗靶点。

LRRK2(Leucine-Rich Repeat Kinase 2)基因突变是最常见的帕金森病遗传风险因素,而 LRRK2 G2019S 位点突变是 LRRK2 中最常见的致病性突变,在家族性帕金森病占比4%-5%,在散发性帕金森病中占比1%。

抑制 LRRK2 活性并由此改善膜运输和溶酶体功能,是一种有前途的帕金森病治疗新方法。此外,除了具有 LRRK2 基因突变的帕金森病患者外,其他遗传形式的帕金森病患者或非遗传性特发性帕金森病患者中同样存在着 LRRK2 活性增加的现象。

来自人类基因组研究和临床前帕金森病动物模型研究显示,溶酶体功能障碍是帕金森病的常见标志,包括 LRRK2 抑制剂在内的旨在改善帕金森病患者溶酶体稳态缺陷的治疗方法,可能对帕金森病的治疗有着重要意义。

早在2012年,基因泰克(Genentech)公司发现了 LRRK2 抑制剂(下图左),Denali Therapeutics 对该化合物进行了改造,开发出了 DNL201(下图右),DNL201 是一款 First in Class、选择性、ATP竞争性、可口服的、可穿越血脑屏障的小分子 LRRK2 抑制剂。

临床前动物模型证实,DNL201 能够抑制 LRRK2 活性,而且 DNL201 对 LRRK2 的抑制在疾病细胞模型中表现出改善的溶酶体功能。在非人灵长类食蟹猴中的实验显示,药理学相关剂量的长期给药与不良反应无关。

在分别对122名健康志愿者和28名帕金森病患者中进行的1/1b期临床试验中,单剂量和多剂量的 DNL201 抑制 LRRK2,结果显示,他们的 LRRK2 水平下降了,且下游溶酶体生物标志物发生了相应改变,且具有良好的耐受性。

在健康志愿者和帕金森病患者中均观察到 DNL201 的强大的穿越血脑屏障的能力。这些数据表明,LRRK2 抑制剂有可能在安全且耐受良好的剂量下修正帕金森病患者的溶酶体功能障碍,并可能降低帕金森病的进展速度。这也提示了 LRRK2 抑制剂可作为帕金森病的治疗方法开展进一步临床试验。

除了 DNL201,Denali Therapeutics 还有一个靶向 LRRK2 抑制剂 DNL151,这两者均以满足进行后续临床试验的眼球,而且,DNL151 的药代动力学特性带来了更灵活的给药方案。

Denali Therapeutics 成立于2015年,并于2017年底在纳斯达克上市,目前市值约30亿美元。研究方向主要是神经系统疾病,包括帕金森病、阿尔茨海默病、额颞叶痴呆、渐冻症、多发性硬化症等。

研发管线中进展最快是 DNL151(帕金森病,靶点为LRRK2)、DNL310(粘多糖贮积症2型,靶点为Iduronate 2-sulfatase)、DNL788(渐冻症、阿尔茨海默病、多发性硬化症,靶点为RIPK1)。

原始出处:

XUECHEN ZHU, et al. Structure of the cytoplasmic ring of the Xenopus laevis nuclear pore complex. SCIENCE, 10 Jun 2022, Vol 376, Issue 6598.

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topicName=CIN)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a9a038523631, createdName=kalseyzl, createdTime=Fri Dec 16 09:19:55 CST 2022, time=2022-12-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1853000, encodeId=514018530008d, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Mon Nov 21 18:19:55 CST 2022, time=2022-11-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1227028, encodeId=da38122e02850, content=学习了,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7c592194322, createdName=1209e435m98(暂无昵称), createdTime=Fri Jun 17 13:48:17 CST 2022, time=2022-06-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1376466, encodeId=5cb113e646635, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Fri Jun 17 03:19:55 CST 2022, time=2022-06-17, status=1, ipAttribution=)]
  4. [GetPortalCommentsPageByObjectIdResponse(id=1657649, encodeId=cd8e165e64951, content=<a href='/topic/show?id=3ca31e71903' target=_blank style='color:#2F92EE;'>#TRA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Tue Oct 18 10:19:55 CST 2022, time=2022-10-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995668, encodeId=4df2199566800, content=<a href='/topic/show?id=992411149e' target=_blank style='color:#2F92EE;'>#2抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1114, encryptionId=992411149e, topicName=2抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=28b7142, createdName=liuquan, createdTime=Thu Nov 03 20:19:55 CST 2022, time=2022-11-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1796078, encodeId=4f951e96078bc, content=<a href='/topic/show?id=8c201e758e5' target=_blank style='color:#2F92EE;'>#translational#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17758, encryptionId=8c201e758e5, topicName=translational)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d81c2500028, createdName=12498561m32(暂无昵称), createdTime=Sun Mar 26 04:19:55 CST 2023, time=2023-03-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1859266, encodeId=064b1859266bf, content=<a href='/topic/show?id=e0a9593596' target=_blank style='color:#2F92EE;'>#DIC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5935, encryptionId=e0a9593596, topicName=DIC)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6f7770, createdName=jeanqiuqiu, createdTime=Sat Feb 04 18:19:55 CST 2023, time=2023-02-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1795956, encodeId=4fcb1e95956d2, content=<a href='/topic/show?id=42211e757d7' target=_blank style='color:#2F92EE;'>#Translation#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17757, encryptionId=42211e757d7, topicName=Translation)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/DYAIOgq83eqPdWFricgmt6Dde2ptNxJzD6Y9c4cxpXdTo4pNlVPARAnFdKu6nWIPele9icxApTaFgibq0uVlgRiceQ/132, createdBy=4b8c2500026, createdName=ms8435843352634314, createdTime=Thu Jun 23 22:19:55 CST 2022, time=2022-06-23, status=1, ipAttribution=), 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topicName=CIN)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a9a038523631, createdName=kalseyzl, createdTime=Fri Dec 16 09:19:55 CST 2022, time=2022-12-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1853000, encodeId=514018530008d, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Mon Nov 21 18:19:55 CST 2022, time=2022-11-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1227028, encodeId=da38122e02850, content=学习了,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7c592194322, createdName=1209e435m98(暂无昵称), createdTime=Fri Jun 17 13:48:17 CST 2022, time=2022-06-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1376466, encodeId=5cb113e646635, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Fri Jun 17 03:19:55 CST 2022, time=2022-06-17, status=1, ipAttribution=)]
    2023-02-04 jeanqiuqiu
  5. [GetPortalCommentsPageByObjectIdResponse(id=1657649, encodeId=cd8e165e64951, content=<a href='/topic/show?id=3ca31e71903' target=_blank style='color:#2F92EE;'>#TRA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Tue Oct 18 10:19:55 CST 2022, time=2022-10-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995668, encodeId=4df2199566800, content=<a href='/topic/show?id=992411149e' target=_blank style='color:#2F92EE;'>#2抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1114, encryptionId=992411149e, topicName=2抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, 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topicName=CIN)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a9a038523631, createdName=kalseyzl, createdTime=Fri Dec 16 09:19:55 CST 2022, time=2022-12-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1853000, encodeId=514018530008d, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Mon Nov 21 18:19:55 CST 2022, time=2022-11-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1227028, encodeId=da38122e02850, content=学习了,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7c592194322, createdName=1209e435m98(暂无昵称), createdTime=Fri Jun 17 13:48:17 CST 2022, time=2022-06-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1376466, encodeId=5cb113e646635, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Fri Jun 17 03:19:55 CST 2022, time=2022-06-17, status=1, ipAttribution=)]
  6. [GetPortalCommentsPageByObjectIdResponse(id=1657649, encodeId=cd8e165e64951, content=<a href='/topic/show?id=3ca31e71903' target=_blank style='color:#2F92EE;'>#TRA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Tue Oct 18 10:19:55 CST 2022, time=2022-10-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995668, encodeId=4df2199566800, content=<a href='/topic/show?id=992411149e' target=_blank style='color:#2F92EE;'>#2抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1114, encryptionId=992411149e, topicName=2抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, 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GetPortalCommentsPageByObjectIdResponse(id=2067627, encodeId=747f206e627e8, content=<a href='/topic/show?id=d0841e75535' target=_blank style='color:#2F92EE;'>#Transl#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17755, encryptionId=d0841e75535, topicName=Transl)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdqq.qlogo.cn/qqapp/101173734/363C99735735B7F4CB11D5F78F580525/100, createdBy=aab22500211, createdName=ms3025846204744509, createdTime=Thu Apr 13 23:19:55 CST 2023, time=2023-04-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1774064, encodeId=30ba1e7406402, content=<a href='/topic/show?id=5f014e1852' target=_blank style='color:#2F92EE;'>#CIN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4718, encryptionId=5f014e1852, topicName=CIN)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a9a038523631, createdName=kalseyzl, createdTime=Fri Dec 16 09:19:55 CST 2022, time=2022-12-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1853000, encodeId=514018530008d, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Mon Nov 21 18:19:55 CST 2022, time=2022-11-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1227028, encodeId=da38122e02850, content=学习了,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7c592194322, createdName=1209e435m98(暂无昵称), createdTime=Fri Jun 17 13:48:17 CST 2022, time=2022-06-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1376466, encodeId=5cb113e646635, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Fri Jun 17 03:19:55 CST 2022, time=2022-06-17, status=1, ipAttribution=)]
  7. [GetPortalCommentsPageByObjectIdResponse(id=1657649, encodeId=cd8e165e64951, content=<a href='/topic/show?id=3ca31e71903' target=_blank style='color:#2F92EE;'>#TRA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Tue Oct 18 10:19:55 CST 2022, time=2022-10-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995668, encodeId=4df2199566800, content=<a href='/topic/show?id=992411149e' target=_blank style='color:#2F92EE;'>#2抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1114, encryptionId=992411149e, topicName=2抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=28b7142, createdName=liuquan, createdTime=Thu Nov 03 20:19:55 CST 2022, time=2022-11-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1796078, encodeId=4f951e96078bc, content=<a href='/topic/show?id=8c201e758e5' target=_blank style='color:#2F92EE;'>#translational#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17758, encryptionId=8c201e758e5, topicName=translational)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d81c2500028, createdName=12498561m32(暂无昵称), createdTime=Sun Mar 26 04:19:55 CST 2023, time=2023-03-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1859266, encodeId=064b1859266bf, content=<a href='/topic/show?id=e0a9593596' target=_blank style='color:#2F92EE;'>#DIC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5935, encryptionId=e0a9593596, topicName=DIC)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6f7770, createdName=jeanqiuqiu, createdTime=Sat Feb 04 18:19:55 CST 2023, time=2023-02-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1795956, encodeId=4fcb1e95956d2, content=<a href='/topic/show?id=42211e757d7' target=_blank style='color:#2F92EE;'>#Translation#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17757, encryptionId=42211e757d7, topicName=Translation)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/DYAIOgq83eqPdWFricgmt6Dde2ptNxJzD6Y9c4cxpXdTo4pNlVPARAnFdKu6nWIPele9icxApTaFgibq0uVlgRiceQ/132, createdBy=4b8c2500026, createdName=ms8435843352634314, createdTime=Thu Jun 23 22:19:55 CST 2022, time=2022-06-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2067627, encodeId=747f206e627e8, content=<a href='/topic/show?id=d0841e75535' target=_blank style='color:#2F92EE;'>#Transl#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17755, encryptionId=d0841e75535, topicName=Transl)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdqq.qlogo.cn/qqapp/101173734/363C99735735B7F4CB11D5F78F580525/100, createdBy=aab22500211, createdName=ms3025846204744509, createdTime=Thu Apr 13 23:19:55 CST 2023, time=2023-04-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1774064, encodeId=30ba1e7406402, content=<a href='/topic/show?id=5f014e1852' target=_blank style='color:#2F92EE;'>#CIN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4718, encryptionId=5f014e1852, topicName=CIN)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a9a038523631, createdName=kalseyzl, createdTime=Fri Dec 16 09:19:55 CST 2022, time=2022-12-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1853000, encodeId=514018530008d, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Mon Nov 21 18:19:55 CST 2022, time=2022-11-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1227028, encodeId=da38122e02850, content=学习了,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7c592194322, createdName=1209e435m98(暂无昵称), createdTime=Fri Jun 17 13:48:17 CST 2022, time=2022-06-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1376466, encodeId=5cb113e646635, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Fri Jun 17 03:19:55 CST 2022, time=2022-06-17, status=1, ipAttribution=)]
    2022-12-16 kalseyzl
  8. [GetPortalCommentsPageByObjectIdResponse(id=1657649, encodeId=cd8e165e64951, content=<a href='/topic/show?id=3ca31e71903' target=_blank style='color:#2F92EE;'>#TRA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Tue Oct 18 10:19:55 CST 2022, time=2022-10-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995668, encodeId=4df2199566800, content=<a href='/topic/show?id=992411149e' target=_blank style='color:#2F92EE;'>#2抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1114, encryptionId=992411149e, topicName=2抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=28b7142, createdName=liuquan, createdTime=Thu Nov 03 20:19:55 CST 2022, time=2022-11-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1796078, encodeId=4f951e96078bc, content=<a href='/topic/show?id=8c201e758e5' target=_blank style='color:#2F92EE;'>#translational#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17758, encryptionId=8c201e758e5, topicName=translational)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d81c2500028, createdName=12498561m32(暂无昵称), createdTime=Sun Mar 26 04:19:55 CST 2023, time=2023-03-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1859266, encodeId=064b1859266bf, content=<a href='/topic/show?id=e0a9593596' target=_blank style='color:#2F92EE;'>#DIC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, 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topicName=CIN)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a9a038523631, createdName=kalseyzl, createdTime=Fri Dec 16 09:19:55 CST 2022, time=2022-12-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1853000, encodeId=514018530008d, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Mon Nov 21 18:19:55 CST 2022, time=2022-11-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1227028, encodeId=da38122e02850, content=学习了,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7c592194322, createdName=1209e435m98(暂无昵称), createdTime=Fri Jun 17 13:48:17 CST 2022, time=2022-06-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1376466, encodeId=5cb113e646635, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Fri Jun 17 03:19:55 CST 2022, time=2022-06-17, status=1, ipAttribution=)]
    2022-11-21 jklm09
  9. [GetPortalCommentsPageByObjectIdResponse(id=1657649, encodeId=cd8e165e64951, content=<a href='/topic/show?id=3ca31e71903' target=_blank style='color:#2F92EE;'>#TRA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Tue Oct 18 10:19:55 CST 2022, time=2022-10-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995668, encodeId=4df2199566800, content=<a href='/topic/show?id=992411149e' target=_blank style='color:#2F92EE;'>#2抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1114, encryptionId=992411149e, topicName=2抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, 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topicName=CIN)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a9a038523631, createdName=kalseyzl, createdTime=Fri Dec 16 09:19:55 CST 2022, time=2022-12-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1853000, encodeId=514018530008d, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Mon Nov 21 18:19:55 CST 2022, time=2022-11-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1227028, encodeId=da38122e02850, content=学习了,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7c592194322, createdName=1209e435m98(暂无昵称), createdTime=Fri Jun 17 13:48:17 CST 2022, time=2022-06-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1376466, encodeId=5cb113e646635, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Fri Jun 17 03:19:55 CST 2022, time=2022-06-17, status=1, ipAttribution=)]
    2022-06-17 1209e435m98(暂无昵称)

    学习了,谢谢分享

    0

  10. [GetPortalCommentsPageByObjectIdResponse(id=1657649, encodeId=cd8e165e64951, content=<a href='/topic/show?id=3ca31e71903' target=_blank style='color:#2F92EE;'>#TRA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Tue Oct 18 10:19:55 CST 2022, time=2022-10-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995668, encodeId=4df2199566800, content=<a href='/topic/show?id=992411149e' target=_blank style='color:#2F92EE;'>#2抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1114, encryptionId=992411149e, topicName=2抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, 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attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7c592194322, createdName=1209e435m98(暂无昵称), createdTime=Fri Jun 17 13:48:17 CST 2022, time=2022-06-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1376466, encodeId=5cb113e646635, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Fri Jun 17 03:19:55 CST 2022, time=2022-06-17, status=1, ipAttribution=)]
    2022-06-17 jichang

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