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:

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."

KANAZAWA, Japan, July 3, 2023 /PRNewswire/ -- Researchers at Kanazawa University report in Science Advances high-speed atomic force microscopy experiments that show the structural and chemical changes in an enzyme thought to play a vital role in modulating the strength of neural connections. Synapses connect neurons allowing the transmission of signals around the neural network. The strength of these connections varies – for instance strengthening or weakening depending on the signals received and how. This synaptic 'plasticity' underlies learning and memory, and the Ca2+/calmodulin-dependent protein kinase II (CaMKII) is known to play a key role. Previous studies have provided some clues to the mechanisms of CaMKII protein activity in these functions but no one had seen these proteins in action. Now, Hideji Murakoshi at the Graduate University of Advanced Studies and the National Institute for Physiological Sciences and Mikihiro Shibata at Kanazawa University and their colleagues have used high speed atomic force microscopy (HS-AFM) to observe the structural dynamics of these proteins for the first time, not only in various states but in three different species. CaMKII is common to a vast range of species from mammals like rats to older, non-mammalian species like the roundworms (C. elegans) and hydra. In particular, certain structural features of the protein are particularly well preserved, including the kinase domain, the regulatory segment that inhibits the activity of the kinase domain and the hub domain. In addition, the protein has binding sites, phosphorylation sites and linker regions; however, the linker region shows a little more variability suggesting that its function and activation mechanisms are more bespoke for the different species. Previous studies had suggested that the regulatory segment's inhibition of the kinase domain is released when Ca2+/calmodulin binds to the regulatory segment. The activated kinase domains then phosphorylate each other, activity that persists even after the Ca2+/calmodulin becomes dissociated, which has been 'hypothesized to be a form of molecular memory', as the researchers describe in their report. Murakoshi, Shibata and their colleagues studied the protein using atomic force microscopy, which feels topologies using a nanoscale tip, like a needle reading a vinyl record, raster scanning the image plane to build up a picture of the sample structure. With HS-AFM, these images are collected quickly enough to record movies of how these structures change. The researchers noted various measures of the proteins size and motion – the gyrus of rotation – as well as reactions such as kinase domain oligomerization (that is, where there is a limited level of polymerization to join molecules into chains) and phosphorylation – the addition of a phosphoryl group (PO3), which can activate enzymes like kinase. They found that the kinase domain was quite mobile, although this decreased with Ca2+/calmodulin binding. The researchers explain this in terms of the binding stabilizing the protein into a particular helical structure called an α helix. They also note that the binding causes the protein to extend 3nm from the hub assembly, which they suggest may be what dissociates the regulatory segment from the active site in the kinase domain. The mobility then increases again with phosphorylation, which the researchers attribute to the protein losing some of the order of the helical structure. Of the three species investigated – the rat, roundworm and hydra – Murakoshi, Shibata and their colleagues found that the kinase domain only oligomerized in the rat. In addition, in the rat, the protein was more resilient to phosphatase, which removes phosphate groups (PO4) from proteins. "In conclusion," they report, "Our findings provide a basis for a deeper understanding of the molecular mechanisms of CaMKIIα activation." Related image Caption High-speed atomic force microscopy image of calmodulin-dependent protein kinase II. This image was taken at 3.3 frames/second. © 2023 Tsujioka, et al., Science Advances. Glossary High-speed atomic force microscope Atomic force microscopy (AFM) 'feels' the topography of surfaces by the increase and decrease of surface forces tugging on a nanoscale tip as changes in surface height change the distance between the tip and the surface. The tip is mounted on a cantilever so that the tiny changes in the force can be read out by the resulting deflection in the cantilever. AFM can resolve structures with subnanometre scale resolution. It has particular advantages for biological studies because it does not require conducting substrates or a current, which are requirements for other primary microscopes with comparable resolutions, such as the scanning tunnelling microscope. For a long time AFM was limited by the time it takes to capture an image of the surface, but this changed when Toshio Ando at Kanazawa University revealed how the tool could be upgraded to high-speed AFM using various modifications to the scanning, deflection detection and other electronic devices, as well as specifications for the cantilever. With high-speed AFM it became possible to capture dynamics at the nanoscale for the first time. Ca2+/calmodulin-dependent protein kinase II Protein kinases are enzymes. They use phosphate sourced from ATP to phosphorylate specific amino acids on target proteins, which leads to changes in the protein's conformation that regulate its biological activity. Ca2+/calmodulin-dependent protein kinase II (CaMK II) is a serine/threonine specific protein kinase, which means it phosphorylates the OH groups on the serine or threonine amino acid residues. It is modulated by Ca2+/calmodulin where calmodulin is simply an abbreviation for calcium modulated protein. The type two Ca2+/calmodulin-dependent protein kinases are multifunctional and are involved in neurotransmitter secretion, transcription factor regulation, and glycogen metabolism. Reference Shotaro Tsujioka, Ayumi Sumino, Yutaro Nagasawa, Takashi Sumikama, Holger Flechsig, Leonardo Puppulin, Takuya Tomita, Yudai Baba, Takahiro Kakuta, Tomoki Ogoshi, Kenichi Umeda, Noriyuki Kodera, Hideji Murakoshi, Mikihiro Shibata. Imaging single CaMKII holoenzymes at work by high-speed atomic force microscopy, Science Advances June 2023. DOI： 10.1126/sciadv.adh1069 URL: Contact Hiroe Yoneda Senior Specialist in Project Planning and Outreach NanoLSI Administrative Office WPI Nano Life Science Institute (WPI-NanoLSI) Kanazawa University Kakuma-machi, Kanazawa 920-1192, Japan Email: [email protected] Tel: +81 (76) 234-4550 About Nano Life Science Institute (WPI-NanoLSI) Nano Life Science Institute (NanoLSI), Kanazawa University is a research center established in 2017 as part of the World Premier International Research Center Initiative of the Ministry of Education, Culture, Sports, Science and Technology. The objective of this initiative is to form world-tier research centers. NanoLSI combines the foremost knowledge of bio-scanning probe microscopy to establish 'nano-endoscopic techniques' to directly image, analyze, and manipulate biomolecules for insights into mechanisms governing life phenomena such as diseases. About Kanazawa University As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities. The University is located on the coast of the Sea of Japan in Kanazawa – a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas. SOURCE Kanazawa University