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TREATING MIGRAINE BY AGONISING TREK1, TREK2 OR HETEROMERS INCLUDING THEM

机译：通过TREK1，TREK2或包括它们的异位异构体来治疗偏头痛

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摘要

Inventors have found that the MT mutation puts an alternative start codon in frame which leads to the translation of a second TRESK fragment. Surprisingly, the 2 gene products, termed MT1 and MT2, have differential dominant negative effects: MT1 targets TRESK while MT2 targets TREK1 and TREK2, members of another subfamily of K2P channels. Furthermore, they have shown that by co-assembling with and inhibiting TREK1 and TREK2, MT2 increases TG excitability. This resolves the contradictory lack of effects of TRESK-C110R which targets only TRESK and not TREK1 or TREK2. Together their results demonstrate that alternative translation initiation is a mechanism initiated by the TRESK-MT mutation which leads to two protein fragments with dominant negative effects on distinct channel targets. The present invention relates to a method for treating migraine in a subject in need thereof comprising a step of administering the subject with a therapeutically effective amount of agonists of: TREK1, TREK2, TRESK-TREK1, TRESK-TREK2 or TREK1-TREK2.

机译：发明人发现，MT突变使备选的起始密码子符合读框，从而导致第二个TRESK片段的翻译。出乎意料的是，这两种称为MT1和MT2的基因产物具有不同的显性负效应：MT1靶向TRESK，而MT2靶向TREK1和TREK2，它们是K2P通道另一个亚家族的成员。此外，他们表明，通过与TREK1和TREK2共同组装并抑制，MT2可以提高TG的兴奋性。这解决了TRESK-C110R仅针对TRESK而未针对TREK1或TREK2的矛盾矛盾。他们的研究结果共同表明，备选翻译起始是由TRESK-MT突变引发的机制，该突变导致两个蛋白片段在不同的通道靶标上具有显性负作用。本发明涉及一种在有需要的受试者中治疗偏头痛的方法，该方法包括给该受试者施用治疗有效量的激动剂：TREK1，TREK2，TRESK-TREK1，TRESK-TREK2或TREK1-TREK2。

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公开/公告号WO2019002548A1

专利类型
公开/公告日2019-01-03

原文格式PDF
申请/专利权人 INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE);CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS);UNIVERSITE NICE SOPHIA ANTIPOLIS;
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申请/专利号WO2018EP67581
发明设计人 LESAGE FLORIAN;SANDOZ GUILLAUME;BARON ANNE;VERKEST CLÉMENT;ROYAL PERRINE;
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申请日2018-06-29
分类号A61K31/404;A61K31/4045;A61K31/405;A61K31/5415;
国家 WO
入库时间 2022-08-21 11:57:29

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