TREK2

Lexicon’s Zynquista (sotagliflozin) is an oral dual inhibitor of the sodium-dependent glucose co-transporter types 1 and 2 (SGLT1 and SGLT2). Image Credit: MacroEcon / Shutterstock. Lexicon Pharmaceuticals reaffirmed its plans to seek approval for Zynquista (sotagliflozin) as an adjunct treatment to insulin in type 1 diabetes (T1D) and chronic kidney disease (CKD) as part of its Q1 financial report. The US-based company expects to resubmit the new drug application (NDA) for Zynquista to the Food and Drug Administration (FDA), following feedback from the agency, by mid-2024. In 2019, the FDA declined to approve the therapy citing safety concerns following a split 8-8 vote from its advisory committee . The FDA advisory committee was particularly concerned about the risk of diabetic ketoacidosis, a serious complication that can become life-threatening if urgent treatment is not administered. The FDA rejection also resulted in Sanofi pulling out of the licensing agreement for Zynquista. Still, Lexicon was able to get approval in 2019 for Zynquista as an adjunctive treatment to insulin in T1D and CKD from the European Medicine Agency (EMA). However, in 2022, the authorisation was withdrawn by the holders of Zynquista’s marketing rights in Europe, Guidehouse Germany, with the company saying it did not wish to “market the product in the EU for commercial reasons”. Zynquista is an oral dual inhibitor of the sodium-dependent glucose co-transporter types 1 and 2 (SGLT1 and SGLT2), which play a role in glucose uptake and reabsorption. The drug was approved by the FDA to reduce the risk of cardiovascular death and heart failure. It was also approved for use in patients with type 2 diabetes, CKD, and other underlying cardiovascular risk factors. It is marketed as Inpefa for the cardiovascular disease indication. See Also: Vertex Pharmaceuticals gets grant for treatment of alpha-1 antitrypsin deficiency with compound of formula (i) Ono Pharmaceutical gets grant for compound for treating disorders associated with TREK-1 and TREK-2 dysfunction Lexicon is also evaluating sotagliflozin as a treatment for hypertrophic cardiomyopathy, with a Phase III trial planned to start in mid-2024. The company has reported $355.6m in cash reserves as of 31 March. If Zynquista gets approved, it will face competition not only from other SGLT-2 inhibitors , including AstraZeneca ’s Farxiga (dapagliflozin), Boehringer Ingelheim’s Jardiance (empagliflozin) and Johnson & Johnson ’s Invokana (canagliflozin), but also from newer innovative therapies such as islet cell transplantation . In June 2023, the FDA approved the first-ever islet cell therapy for T1D, CellTrans’ Lantidra (donislecel). Other therapies in Lexicon’s portfolio include LX9211, a non-opioid therapy for diabetic peripheral neuropathic pain; and LX9851, a treatment for obesity and weight management. The company is evaluating LX9211 in a Phase II PROGRESS trial (NCT06203002), with the topline data expected in Q2 2025.

引言即使没有高血糖症，糖尿病前期也可能发生神经性疼痛。糖尿病前期神经性疼痛（PDNP）的存在给糖尿病前期患者的治疗带来了难题。然而，仍不清楚这一疼痛背后的作用机制。2024年4月16日，空军军医大学陈俊及武俊杰共同通讯在Advanced Science 在线发表题为“Sortilin-Mediated Inhibition of TREK1/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain”的研究论文，该研究旨在探讨PDNP的发生机制并确定潜在的治疗靶点。由高能量饮食诱导的糖尿病前期动物模型表现出异常性机械疼痛和热痛觉过敏。此外，这些大鼠的背根神经节（DRG）神经元中出现过度兴奋和钾电流减少。TREK1和TREK2通道属于双孔结构域K+通道（K2P）家族，在控制细胞兴奋中起重要作用，但在DRG神经元中出现下调。研究发现，这一改变由Sortilin调控，Sortilin是一种调节TREK1表达的分子伴侣。Sortilin的过表达对TREK1和TREK2的表达产生负面影响，导致大鼠DRG神经元兴奋性增加和外周疼痛敏感性增强，通过遗传或药理学方法下调Sortilin或激活TREK1/TREK2通道可以缓解PDNP。因此，靶向Sortilin介导的TREK1/2通路为改善PDNP提供了一种潜在治疗方法。葡萄糖耐受异常（IGT）或胰岛素抵抗受损但不符合II型糖尿病诊断标准的个体通常被认为是糖尿病前期。据报道，在葡萄糖代谢障碍的初始阶段会出现神经病变。与糖尿病神经性并发症仅在长期高血糖后发生的观点相反，糖尿病前期神经病变（PDN）出现在高血糖发作之前。此外，部分研究强调了糖尿病前期慢性轴突多发性神经病变的发生，这是神经性疼痛的主要原因，也是糖尿病足溃疡的起始因素。因此，许多糖尿病前期患者可能会出现周围神经病变或神经性疼痛，其特征是周围神经的远端到近端变性，导致疼痛、虚弱和最终的感觉丧失。大约50-60%的糖尿病前期患者患有持续性糖尿病前期神经性疼痛（PDNP），由于缺乏对PDNP发生机制的了解，仍缺乏有效的治疗方法。高能量饮食（HED）诱导的糖尿病前期动物模型具有可重复性和临床相关性，被广泛用于探索糖尿病前期和PDNP的发病机制。HED喂养后，大鼠逐渐出现IGT和胰岛素浓度升高，还出现明显的疼痛性神经病变和神经传导缺陷。然而，过去几十年中，缺乏神经电生理学和组织学数据来证明糖尿病前期存在PDNP。近年来，相关学者对糖尿病前期周围神经的形态特征进行了研究。结果表明，髓鞘是松散的，无序的，部分破裂成囊泡样膜碎片。此外，超微结构病理研究表明无髓鞘神经纤维中存在轴突病变。几项调查糖尿病前期神经功能的研究报道轴突中Ca2+水平显著降低、神经传导延缓且周围神经系统（PNS）中神经元线粒体功能受损。糖尿病前期相关神经病变的发展也可能受到复杂致病因素的影响。目前，仍不清楚PDNP背后的分子机制。DRG神经元中TREK1表达谱的特征表明，糖尿病前期大鼠NF200、IB4和CGRP阳性神经元中TREK1的表达降低（Credit: Advanced Science ）电压依赖性Na+和K+通道的顺序激活可影响神经兴奋性和膜活性特性，也是参与去极化和复极化的两种重要离子通道。双孔域K+通道（K2P）是K+通道的重要分支，是钾电流的主要关联分子，在控制细胞兴奋性方面发挥重要作用。哺乳动物中，K2P家族由15个不同成员组成，根据序列相似性分为6个亚家族。其中，TWIK相关的K1通道（TREK）亚家族在神经系统中广泛表达，尤其是在PNS中，包括三个成员：TREK-1、TREK-2和TWIK相关花生四烯酸激活的K1通道（TRAAK）。这些亚家族成员表现出超过78%的序列同源性，且部分激活机制相同，能够被膜拉伸和肿胀、细胞酸化（pHi）、温度升高、多不饱和脂肪酸（如花生四烯酸、溶血磷脂和磷脂酰肌醇4，5-二磷酸）以及挥发性麻醉剂（如氟烷和异氟烷）激活。因此，这些通道在麻醉、神经保护、抑郁和疼痛等多种生理和病理过程中发挥作用。就细胞电生理特性而言，三个K2P通道对DRG神经元中的背景K+电流具有显著影响，其主要发生器是TREK2通道（69%），其次是TREK-1通道（12%）和TRAAK通道（3%）。近期证据表明，各种TREK通道在慢性疼痛的处理过程中起着至关重要的作用。利用转基因技术，相关学者发现缺乏TREK1或TREK2通道的小鼠对热和机械刺激都表现出超敏反应。疼痛动物模型研究表明，TREK1和TREK2通道在调节各种情况下的伤害感受性超敏反应中起着至关重要的作用，如偏头痛、脊神经结扎（SNL）诱导的神经性疼痛、福尔马林诱导的炎性疼痛、前列腺炎疼痛和奥沙利铂诱导的疼痛。因此，TREK1和TREK2通道可以作为镇痛的分子靶点。然而，尚不清楚TREK1和TREK2通道在糖尿病前期引起的神经病理性疼痛中的作用机制。此外，细胞内分选和支架蛋白可以调节TREK通道的表达，如Sortilin、微管相关蛋白2和外壳蛋白复合物1是TREK1表达的潜在调节因子。Sortilin是一种分选蛋白，在中枢神经系统（CNS）和其他细胞类型（如脂肪细胞、肝细胞和巨噬细胞）中大量表达，在蛋白质运输和葡萄糖及脂质代谢调节中起关键作用。据报道，神经系统中Sortilin可调节皮质神经元膜上TREK1的表达，并作为分子抗抑郁药的靶点。然而，尚不完全清楚Sortilin调节糖尿病前期DRG神经元中TREK1和TREK2表达的机制。总之，调控感觉神经元中TREK1/2通道的表达可能会影响神经元兴奋性和伤害感受，，其可视为治疗疼痛的潜在治疗靶点。该研究确定了TREK1和TREK2在PDNP中的作用，并研究了Sortilin在这些通道中的调节作用。结果表明，Sortilin过表达导致TREK1和TREK2表达降低，有助于调控糖尿病前期大鼠的神经过度兴奋性和伤害感受性超敏反应。原文链接https://onlinelibrary.wiley.com/doi/10.1002/advs.202310295责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

BOSTON, Feb. 27, 2024 (GLOBE NEWSWIRE) -- Cerevance, a company focused on developing precision novel therapeutics for central nervous system (CNS) diseases, today announced plans to present a virtual and onsite poster at the upcoming AD/PD™ 2024 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders, taking place in Lisbon, Portugal from March 5-9, 2024. Presentation details Title: NETSseq reveals deep molecular insights into astrocyte biology and identifies novel therapeutic targets for Alzheimer’s disease Overview: The NETSseq platform produces deep transcriptomic and epigenomic profiles from post-mortem human brain tissue. This technology has revealed novel understandings of astrocyte-specific mechanisms influencing disease progression, including a network of genes involved in glutamate signaling that are down-regulated in diseased and activated astrocytes. One of these genes, KCNK10, is specifically expressed in astrocytes and oligodendrocytes, and its role in regulating glutamate uptake has been validated. Modulating KCNK10 activity might mitigate neuronal hyperexcitability and neurodegeneration associated with Alzheimer’s disease. Presenters: Xiao Xu Session and Date and Time: A02.N. Therapeutic Targets, Mechanisms for Treatment: Astroglia; Poster Shift 2: Friday, March 8 - Saturday, March 9, 2024 Poster Number: 0126 About Cerevance Cerevance is focused on the development of precision treatments for central nervous system (CNS) disorders, prioritizing chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis (ALS). Utilizing a large and growing collection of over 14,000 human brain tissue samples, Cerevance is generating an unprecedented level of expression and epigenetic data thereby enabling the company to identify the most promising targets for the next generation of treatments for CNS disorders. The company uses its proprietary NETSseq platform and advanced machine learning techniques to uncover the gene expression profiles of select cell types to identify novel targets that are uniquely expressed in relevant circuits affected by diseases or are altered in disease states. With the information obtained from its research, combined with the expertise of its team of scientists and drug developers, Cerevance is advancing multiple therapeutics that selectively modulate the discovered targets. These treatments are progressing through clinical development, with CVN424, CVN766, and CVN293 being the furthest along in the pipeline. CVN424 is a first-in-class non-dopamine therapy that shows promise in improving both motor and non-motor symptoms of Parkinson's disease and may also have disease-delaying effects. CVN766 is a potent antagonist of the orexin 1 receptor with high selectivity over the orexin 2 receptor which may benefit a variety of psychiatric conditions including schizophrenia, anxiety/panic, binge eating/obesity, substance use disorder, and Prader-Willi Syndrome. CVN293 is a novel blocker of potassium efflux in glia, regulating the inflammasome in individuals living with ALS and Alzheimer's disease. Cerevance’s robust pipeline aims to transform the lives of patients affected by CNS diseases. Contacts Cerevance: Johnna Simoes, ir@cerevance.com Media: Andrew Mielach, amielach@lifescicomms.com, +1-646-876-5868