GluK2

Researchers have identified the protein that enables mammals to sense cold, filling a long-standing knowledge gap in the field of sensory biology. University of Michigan researchers have identified the protein that enables mammals to sense cold, filling a long-standing knowledge gap in the field of sensory biology. The findings, published in Nature Neuroscience, could help unravel how we sense and suffer from cold temperature in the winter, and why some patients experience cold differently under particular disease conditions. "The field started uncovering these temperature sensors over 20 years ago, with the discovery of a heat-sensing protein called TRPV1," said neuroscientist Shawn Xu, a professor at the U-M Life Sciences Institute and a senior author of the new research. "Various studies have found the proteins that sense hot, warm, even cool temperatures -- but we've been unable to confirm what senses temperatures below about 60 degrees Fahrenheit." In a 2019 study, researchers in Xu's lab discovered the first cold-sensing receptor protein in Caenorhabditis elegans, a species of millimeter-long worms that the lab studies as a model system for understanding sensory responses. Because the gene that encodes the C. elegans protein is evolutionarily conserved across many species, including mice and humans, that finding provided a starting point for verifying the cold sensor in mammals: a protein called GluK2 (short for Glutamate ionotropic receptor kainate type subunit 2). For this latest study, a team of researchers from the Life Sciences Institute and the U-M College of Literature, Science, and the Arts tested their hypothesis in mice that were missing the GluK2 gene, and thus could not produce any GluK2 proteins. Through a series of experiments to test the animals' behavioral reactions to temperature and other mechanical stimuli, the team found that the mice responded normally to hot, warm and cool temperatures, but showed no response to noxious cold. GluK2 is primarily found on neurons in the brain, where it receives chemical signals to facilitate communication between neurons. But it is also expressed in sensory neurons in the peripheral nervous system (outside the brain and spinal cord). "We now know that this protein serves a totally different function in the peripheral nervous system, processing temperature cues instead of chemical signals to sense cold," said Bo Duan, U-M associate professor of molecular, cellular, and developmental biology and co-senior author of the study. While GluK2 is best known for its role in the brain, Xu speculates that this temperature-sensing role may have been one of the protein's original purposes. The GluK2 gene has relatives across the evolutionary tree, going all the way back to single-cell bacteria. "A bacterium has no brain, so why would it evolve a way to receive chemical signals from other neurons? But it would have great need to sense its environment, and perhaps both temperature and chemicals," said Xu, who is also a professor of molecular and integrative physiology at the U-M Medical School. "So I think temperature sensing may be an ancient function, at least for some of these glutamate receptors, that was eventually co-opted as organisms evolved more complex nervous systems." In addition to filling a gap in the temperature-sensing puzzle, Xu believes the new finding could have implications for human health and well-being. Cancer patients receiving chemotherapy, for example, often experience painful reactions to cold. "This discovery of GluK2 as a cold sensor in mammals opens new paths to better understand why humans experience painful reactions to cold, and even perhaps offers a potential therapeutic target for treating that pain in patients whose cold sensation is overstimulated," Xu said. The research was supported by the National Institutes of Health. All procedures performed in mice were approved by the Institutional Animal Care and Use Committee and performed in accordance with the institutional guidelines. Study authors are: Wei Cai, Wenwen Zhang, Chia Chun Hor, Tong Pan, Mahar Fatima, Bo Duan and X.Z. Shawn Xu of the University of Michigan; and Qin Zheng and Xinzhong Dong of the Johns Hopkins University School of Medicine

LEXINGTON, Mass. and AMSTERDAM, Oct. 24, 2023 (GLOBE NEWSWIRE) -- uniQure N.V. (NASDAQ: QURE), a leading gene therapy company advancing transformative therapies for patients with severe medical needs, today announced that 12 data presentations, including two oral presentations, will be delivered at the European Society of Gene and Cell Therapy (ESGCT) Annual Meeting being held October 24-27 in Brussels, Belgium. “Our multiple presentations at ESGCT demonstrate uniQure’s continued leadership in advancing important research within the field of gene therapy, as well as highlight our industry-leading expertise in AAV gene therapy manufacturing,” stated Richard Porter, Ph.D., Chief Business and Scientific Officer at uniQure. “We look forward to sharing these presentations that feature our technology and platform experience across numerous programs.” Specific details on uniQure’s presentations taking place at ESGCT include: Invited Talk Title: Update on U.S. Phase I/II Clinical Trial of AMT-130 Gene Therapy for the Treatment of Huntington’s DiseasePresenter: Richard Porter, Chief Business and Scientific Officer, uniQureSession Title and Location: CNS & sensory diseases II, Session 10a, Shed 2ADate and Time: Friday, October 27, 8:30 a.m. GMT+2 Title: Gene therapy for C9ORF72-ALS reduces RNA toxicity and ameliorates behavioral phenotype in ALS mouse modelPresenter: Vanessa Zancanella, Sr. Scientist Global Research, uniQureSession Title and Location: CNS & sensory diseases I, Session 2c, Maison de la PosteDate and Time: Tuesday, October 24, 17:00 – 19:00 GMT+2 Title: Pivotal safety studies for AMT-260, a novel AAV9-dual microRNA-based vector targeting GRIK2 for the treatment of temporal lobe epilepsy (Poster #433)Presenter: Nick Pearson, Sr. Director Toxicology & Translational Safety, Non-Clinical, uniQure Poster Session Date and Time: Wednesday, October 25, 17:00 – 18:15, Thursday, October 26, 20:30 – 21:30 GMT+2 Title: Production of low cross-packaging AAV capsid libraries in insect cells (Poster #166)Presenter: Bas Bosma, Scientific Leader, Technology Innovation, uniQurePoster Session Date and Time: Wednesday, October 25, 18:15 – 19:30, Thursday October 26, 19:30 – 20:30 GMT+2 Title: Multiplexed comparison of rationally-designed AAV CNS capsids in vivo (Poster #181)Presenter: Elena Pimentel, Scientist, Technology Innovation, uniQurePoster Session Date and Time: Wednesday, October 25, 17:00 – 18:15, Thursday, October 26, 20:30 – 21:30 GMT+2 Title: Silence and replace as potential treatment for Alzheimer Disease: in concert lowering toxic APOE and augmenting protective APOE (Poster #049)Presenter: Amila Zuko, Scientist, Global Research, uniQurePoster Session Date and Time: Wednesday, October 25, 17:00 – 18:15, Thursday, October 26, 20:30 – 21:30 GMT+2 Title: Gene therapy for synucleinopathies: Combining vectorized antibody and miRNA-mediated lowering strategies (Poster #430)Presenter: Kim Wolzak, Jr. Scientist, Global Research, uniQurePoster Session Date and Time: Wednesday, October 25, 18:15-19:30, Thursday, October 26, 19:30-20:30 GMT+2 Title: Alpha-synuclein lowering and rescue of motor phenotype by miRNA-based AAV gene therapy in an in vivo Parkinson’s disease rat model (Poster #420)Presenter: Rhodé van Westen Erbrink, Scientist, Global Research, uniQurePoster Session Date and Time: Wednesday, October 25, 18:15-19:30, Thursday, October 26, 19:30-20:30 GMT+2 Title: How uniQure’s modular platform approach drives continuous innovation in AAV gene therapy development and manufacturing (Poster #329)Presenter: Erich Ehlert, Director – Process Development – Chemistry, Manufacturing and Controls, uniQurePoster Session Date and Time: Wednesday, October 25, 17:00-18:15, Thursday, October 26, 20:30-21:30 GMT+2 Title: Accelerating process development by establishing drug substance development platform (Poster #191)Presenter: Giorgio Rainone, Bioprocess Technologist, Drug Substance Development, uniQurePoster Session Date and Time: Wednesday, October 25, 17:00-18:15, Thursday, October 26, 20:30-21:30 GMT+2 Title: High-throughput process development in rAAV drug substance manufacturing (Poster #308)Presenter: Yang Jiang, Associate Director, Drug Substance Development, uniQurePoster Session Date and Time: Wednesday, October 25, 18:15-19:30, Thursday, October 26, 19:30-20:30 GMT+2 Title: Platform development for AAV manufacturing with the Baculovirus Expression Vector System (BEVS) (Poster #193)Presenter: Zandra Félix Garza, Project Manager- BPU – Cells, Seeds and Research Supply, uniQurePoster Session Date and Time: Wednesday, October 25, 17:00-18:15, Thursday, October 26, 20:30-21:30 GMT+2 About uniQure uniQure’s mission is to reimagine the future of medicine by delivering innovative cures that transform lives. The recent approvals of our gene therapy for hemophilia B – an historic achievement based on more than a decade of research and clinical development – represent a major milestone in the field of genomic medicine and ushers in a new treatment approach for patients living with hemophilia. We are now leveraging our modular and validated technology and manufacturing platform to advance a pipeline of proprietary gene therapies for the treatment of patients with Huntington's disease, refractory mesial temporal lobe epilepsy, amyotrophic lateral sclerosis (ALS), Fabry disease, and other severe diseases. www.uniQure.com uniQure Contacts: FOR INVESTORS:Chiara RussoDirect: 617-306-9137Mobile: 617-306-9137c.russo@uniQure.comFOR MEDIA:Tom MaloneDirect: 339-970-7558Mobile:339-223-8541 t.malone@uniQure.com

Clinical trial initiation expected in the fourth quarter of 2023LEXINGTON, Mass. and AMSTERDAM, Sept. 05, 2023 (GLOBE NEWSWIRE) -- uniQure N.V. (NASDAQ: QURE), a leading gene therapy company advancing transformative therapies for patients with severe medical needs, today announced that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) application for AMT-260, the Company’s gene therapy candidate for refractory mesial temporal lobe epilepsy (MTLE). AMT-260 comprises an AAV9 vector that locally delivers two engineered miRNAs designed to degrade the GRIK2 gene and suppress the aberrant expression of glutamate receptor subtype GLUK2 that is believed to trigger seizures in patients with refractory MTLE. “The clearance of the IND for AMT-260 is an important achievement in advancing our pipeline and is our next program to enter clinical development in an area of high unmet medical need,” stated Walid Abi-Saab, chief medical officer of uniQure. “There are few treatment options for patients who have refectory MTLE, and we are pleased to soon begin the clinical investigation of this one-time administered gene therapy approach as a potential new treatment.” The first-in-human Phase I/IIa clinical trial will be conducted in the United States and consist of two parts. The first part is a multicenter, open-label trial with two dosing cohorts of six patients each to assess safety, tolerability, and first signs for efficacy of AMT-260 in patients with refractory MTLE. The second part is expected to be a randomized, controlled trial to generate proof of concept (POC) data. The clinical trial is expected to begin patient screening in the fourth quarter of 2023. About AMT-260AMT-260 is an AAV9 gene therapy product that locally delivers miRNA silencing technology to target the GRIK2 gene and suppress aberrantly expressed GluK2 containing kainate receptors. The therapeutic goal is to lower the expression of GluK2 containing kainate receptors which are believed to trigger epilepsy when aberrantly expressed in the epileptic hippocampus. AMT-260 represents a novel potential one-time administered approach to treating refractory MTLE. About Refractory Mesial Temporal Lobe EpilepsyTemporal lobe epilepsy is a chronic neurologic disorder and is the most common form of focal epilepsy with more than 600,000 individuals suffering from the disorder in the United States. Approximately 80% of all temporal lobe epilepsy cases are mesial, which involves the medial or internal structures. The majority of MTLE cases are refractory to anti-seizure medications which severely limits treatment options. About uniQure uniQure’s mission is to reimagine the future of medicine by delivering innovative cures that transform lives. The recent approvals of our gene therapy for hemophilia B – a historic achievement based on more than a decade of research and clinical development – represents a major milestone in the field of genomic medicine and ushers in a new treatment approach for patients living with hemophilia. We are now leveraging our modular and validated technology and manufacturing platform to advance a pipeline of proprietary gene therapies for the treatment of patients with Huntington's disease, refractory mesial temporal lobe epilepsy, amyotrophic lateral sclerosis (ALS), Fabry disease, and other severe diseases. www.uniQure.com uniQure Forward-Looking Statements This press release contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as "anticipate," "believe," "could," “establish,” "estimate," "expect," "goal," "intend," "look forward to", "may," "plan," "potential," "predict," "project," “seek,” "should," "will," "would" and similar expressions. Forward-looking statements are based on management's beliefs and assumptions and on information available to management only as of the date of this press release. These forward-looking statements include, but are not limited to, statements regarding the timing of patient enrollment in the Company’s open-label U.S. Phase I/IIa trial for refractory MTLE and the scope of treatment options for patients who have refractory MTLE. The Company’s actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, risks associated with the impact of financial and geopolitical events on our Company and the wider economy and health care system, our clinical development activities, clinical results, collaboration arrangements, regulatory oversight, product commercialization and intellectual property claims, as well as the risks, uncertainties and other factors described under the heading "Risk Factors" in the Company’s periodic securities filings, including its Annual Report on Form 10-K filed February 27, 2023 and the Quarterly Report on Form 10-Q filed August 1, 2023. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and the Company assumes no obligation to update these forward-looking statements, even if new information becomes available in the future. uniQure Contacts: FOR INVESTORS: FOR MEDIA: Maria E. Cantor Chiara Russo Tom MaloneDirect: 339-970-7536 Direct: 617-306-9137 Direct: 339-970-7558Mobile: 617-680-9452 Mobile: 617-306-9137 Mobile:339-223-8541m.cantor@uniQure.com c.russo@uniQure.com t.malone@uniQure.com