CAMK2A

LONDON--(BUSINESS WIRE)-- EpilepsyGTx, a biotechnology company focused on research and development of cutting-edge gene therapies to treat focal refractory epilepsy, today announced it has raised a total of $10 million in seed funding. The financing was led by the UCL Technology Fund, with participation from Health Technology Holding. The funds raised will be used to complete the preclinical studies for EpilepsyGTx’ lead gene therapy program EPY201, and to prepare a groundbreaking first-in-human, Phase 1/2a clinical study with EPY201 in focal refractory epilepsy. "This funding is a clear vote of confidence from our investors in our vision, the world-class science of the UCL Queen Square Institute of Neurology, and the transformative potential of EPY201 in focal refractory epilepsy. Our mission is to make patients with focal refractory epilepsy seizure-free," said Nicolas Koebel, chief executive officer. Simon Goldman, Partner at AlbionVC, manager of the UCL Technology Fund and EpilepsyGTx Board member, added, “EpilepsyGTx has an objectively world-leading pipeline of genetic therapies for a common and damaging neurological disorder with few treatment options, developed by a globally-renowned clinical, scientific and translational team at the UCL Queen Square Institute of Neurology. We are enormously pleased to have Nicolas Koebel on board as CEO, with a track record of building exceptional global biotech companies from inception to commercial launch. We are excited that this industry-leading team now has the opportunity to translate medicines that have the potential to change the lives of patients with epilepsy and other CNS disorders.” EpilepsyGTx is a spinout company set up with the support of UCL’s commercialisation company UCL Business Ltd (UCLB). Caitriona O’Rourke, UCLB’s Business Manager for EpilepsyGTx commented: “We have been delighted to support Nicolas and his team on their commercialisation journey, and it’s terrific to see them reach this major funding milestone. We are excited by the commercial potential of this technology and its possible contribution to improve the lives of people with focal refractory epilepsy.” Michele Gaiotto, Managing Director at Health Technology Holding, stated, “We were highly impressed by the scientific strategy of the company and the credentials of the leadership team. The targeted, highly localized delivery of gene therapy is the right solution to treat focal refractory epilepsy, and is poised to make an enormous difference in the lives of millions of patients.” About EpilepsyGTx At EpilepsyGTx our mission is to make patients with focal refractory epilepsy seizure-free. We are developing a portfolio of cutting-edge gene therapies which are based on pioneering research from the UCL Queen Square Institute of Neurology. For more information, please visit: About focal refractory epilepsy Focal epilepsy describes a group of disorders in which patients experience seizures that arise from a specific part of the brain. If seizures persist despite trials of at least two tolerated and appropriately chosen antiseizure medicines, epilepsy is deemed refractory. Focal refractory epilepsy (or FRE) affects an estimated 2 million prevalent patients in the United States, the United Kingdom and the European Union, combined. About EPY201 EPY201 is an investigational gene therapy targeting focal refractory epilepsy. EPY201 or AAV9-CAMK2A-EKC uses an AAV9 capsid, an engineered Kv1.1 potassium channel (or “EKC”) and a CAMK2A promoter. EPY201 is delivered directly to the target seizure focus (that is, the part of the brain causing seizures) by intraparenchymal administration. About UCL Technology Fund The UCL Technology Fund exists to help solve the world’s most pressing problems: healthy planet, healthy people and healthy work. It helps UCL innovators across the Physical and Life Sciences scale globally. The Fund supports UCL in achieving the full potential of innovations that have prospects for outstanding societal and market impact, right through the development journey from initial proof of concept to practical commercial application. The Fund is managed by AlbionVC in collaboration with UCL Business. For further information please visit: View source version on businesswire.com: Contacts For enquiries, please contact: communications@epilepsygtx.com Phone: +44 7717 801 246 Source: EpilepsyGTx View this news release online at:

*仅供医学专业人士阅读参考糖酵解是指在无氧条件下葡萄糖被分解为丙酮酸的过程，每分解一分子的葡萄糖，产生两分子的丙酮酸和两分子的ATP，以此为细胞提供能量。糖酵解是细胞代谢的重要途径，有氧糖酵解也是神经元中葡萄糖代谢的主要方式[1]。但是，神经元中的糖酵解水平却很低，形成了能量悖论。来自西班牙萨拉曼卡大学的研究人员利用小鼠模型，对神经元中的糖酵解水平以及相关代谢通量进行了分析。结果发现，高神经元糖酵解水平的小鼠出现了线粒体异常积聚、复合物I分解、线粒体氧化还原应激等问题。并且，研究人员还发现小鼠出现了认知下降和代谢综合征。消除神经元的线粒体氧化还原应激或恢复大脑NAD+水平可以改善小鼠的认知障碍。研究发表在《自然·代谢》上[2]。6-磷酸果糖-2-激酶/2,6-二磷酸果糖酶-3（PFKFB3）是参与糖酵解调节的关键酶，与葡萄糖代谢速率有关。CDH1是泛素连接酶APC/C的辅助因子，高APC/C活性会导致PFKFB3蛋白的不稳定，从而导致神经元中糖酵解的降低。在AD患者神经元中可以观察到糖酵解水平异常升高。因此，研究人员构建了神经元PFKFB3表达升高的CamkIIα-Pfkfb3小鼠模型。PFKFB3水平增加的神经元具有更高的糖酵解通量，但同时线粒体ROS增加，表现出氧化还原应激。神经元特异性PFKFB3表达激活糖酵解并导致氧化还原应激通过对PFKFB3神经元的线粒体功能进行评估，研究人员发现，线粒体复合物I（CI）活性受损，ATP相关氧消耗率受损，其他代谢途径也受到影响，葡萄糖消耗和乳酸生成的速率分别是之前的约2.5倍和1.3倍，丙酮酸到乳酸的转化率随着PFKFB3水平升高而升高，但是NAD+水平并没有随之升高，表明再生NAD+的能力受损。同时，CamkIIα-Pfkfb3小鼠神经元功能标志物减少，海马和下丘脑的神经元凋亡增加，免疫细胞化学分析显示海马神经元的完整性被破坏。而小鼠行为也发生了一系列变化，比如在旷场实验中表现出恐惧和焦虑，运动能力和耐力下降，并且在新型物体识别测试中表现出短期认知障碍。CamkIIα-Pfkfb3小鼠认知功能受损神经元PFKFB3水平升高对小鼠的影响还体现在其他方面。在小鼠8个月时，体重相比于野生型小鼠显著增加，皮下和腹部的白色脂肪及棕色脂肪增加，肝脏增大，并出现肌肉减少症，血浆甘油三酯、瘦素、胰岛素水平也受到影响，无法在葡萄糖耐受性测试中降低血浆葡萄糖水平，下丘脑内侧基底节自噬通量受损。在神经元中过表达mCat基因调节PFKFB3水平，可以缓解PFKFB3过表达所引起的种种负面效应，小鼠代谢紊乱、体重增加、神经元功能障碍和认知下降等均有所好转。总的来说，研究发现神经元保持低糖酵解活性以保证NADPH的生成，从而维护神经元的抗氧化能力、保护神经元免受氧化应激引起的线粒体损伤。当神经元中线粒体功能受损时，NAD+的再生能力受损，会导致自噬受损和小鼠认知缺陷。这个机制可以解释阿尔茨海默病等疾病中异常升高的糖酵解活性，抑制神经元特异性PFKFB3表达可能是潜在的治疗策略。参考文献：[1]https://www.nature.com/articles/s41593-023-01476-4[2]Jimenez-Blasco D, Agulla J, Lapresa R, et al. Weak neuronal glycolysis sustains cognition and organismal fitness[J]. Nature Metabolism, 2024: 1-15.本文作者丨王雪宁

Major depressive disorder (MDD) is a widespread mental health condition that for many is disabling. It has long been appreciated that MDD has genetic as well as environmental influences. In a new study researchers identify a gene that interacted with stress to mediate aspects of treatment-resistant MDD in an animal model. Major depressive disorder (MDD) is a widespread mental health condition that for many is disabling. It has long been appreciated that MDD has genetic as well as environmental influences. In a new study in Biological Psychiatry, published by Elsevier, researchers identify a gene that interacted with stress to mediate aspects of treatment-resistant MDD in an animal model. Jing Zhang, PhD, at Fujian Medical University and senior author of the study, said, "Emerging evidence suggests that MDD is a consequence of the co-work of genetic risks and environmental factors, so it is crucial to explore how stress exposure and risk genes co-contribute to the pathogenesis of MDD." To do that, the authors used a mouse model of stress-induced depression called chronic social defeat stress (CSDS) in which mice are exposed to aggressor mice daily for two weeks. They focused on a gene called LHPP, which interacts with other signaling molecules at neuronal synapses. Increased expression of LHPP in the stressed mice aggravated the depression-like behaviors by decreasing expression of BDNF and PSD95 by dephosphorylating two protein kinases, CaMKIIα and ERK, under stress exposure. Dr. Zhang noted, "Interestingly, LHPP mutations (E56K, S57L) in humans can enhance CaMKIIα/ERK-BDNF/PSD95 signaling, which suggests that carrying LHPP mutations may have an antidepressant effect in the population." MDD is an extremely heterogeneous condition. Differences in the types of depression experienced by people influence the way they respond to treatment. A large subgroup of people with depression fail to respond to standard antidepressant medications and have "treatment-resistant" symptoms of depression. These patients often respond to different medications, such as ketamine or esketamine, or to electroconvulsive therapy. Notably, esketamine markedly alleviated LHPP-induced depression-like behaviors, whereas the traditional drug fluoxetine did not, suggesting that the mechanism might underlie some types of treatment-resistant depression. John Krystal, MD, Editor of Biological Psychiatry, said of the work, "We have limited understanding of the neurobiology of treatment-resistant forms of depression. This study identifies a depression risk mechanism for stress-related behaviors that fail to respond to a standard antidepressant but respond well to ketamine. This may suggest that the risk mechanisms associated with the LHPP gene shed light on the poorly understood biology of treatment-resistant forms of depression." Dr. Zhang added, "Together, our findings identify LHPP as an essential player driving stress-induced depression, implying targeting LHPP as an effective strategy in MDD therapeutics in the future."