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EDINBURGH, Scotland--( BUSINESS WIRE )--Lario Therapeutics (‘Lario’, or ‘the Company’), a biopharmaceutical company developing first-in-class precision medicines for epileptic and neurological disorders, today announced it has been awarded a $6 million USD grant from The Michael J. Fox Foundation for Parkinson’s Research (MJFF). The programme is in collaboration with the Oxford Parkinson’s Disease Centre, which will also be delivering key science as part of the grant. The grant will be used to fund Lario’s preclinical programme investigating selective CaV2.3 calcium channel inhibition as a novel and disease-modifying approach for treatment of Parkinson’s disease. There is extensive literature linking calcium channels to pathology of the disease, and it has been demonstrated in preclinical experimental studies that the deletion of CaV2.3 can have a protective effect against Parkinson’s disease progression. Lario is partnering with Professor Richard Wade-Martins and the Oxford Parkinson’s Disease Centre (OPDC) for the study, for the evaluation of Lario compounds in state-of-the-art patient-derived stem cell models of Parkinson’s disease. Parkinson’s disease is a progressive neurodegenerative disorder occurring when brain cells that make dopamine, which coordinates movement, stop working or die. Symptoms are lifelong and worsen over time, including motor disfunction, such as tremor, slowness, stiffness, walking and balance problems, as well as problems such as depression and memory problems. More than 10 million people worldwide are estimated to be living with Parkinson’s, with no current cure. Tom Otis, Ph.D., Professor of Neuroscience UCL and Chief Scientific Officer of Lario Therapeutics, said: “ We are grateful to MJFF for their funding support for Lario’s efforts to test and develop a potential new therapy designed to prevent the loss of neurons that causes Parkinson’s disease. If our research is successful, this will represent an important new treatment option for patients.” “This significant funding from The Michael J. Fox Foundation will aid the work out of our therapeutic pipeline and the work we have achieved so far in advancing research in the field. We would like to thank the MJFF team for their support,” added Henning Steinhagen, Ph.D., Co-Founder and CEO of Lario Therapeutics. “This grant will help drive our ambition to progress our Cav2.3 program swiftly towards the clinic, to provide a new, effective treatment option for people with Parkinson’s disease.” “ MJFF is dedicated to funding innovative research, such as the work done at Lario Therapeutics, to develop a pipeline of novel therapies that can improve the lives of people with Parkinson’s disease ,” said Gaia Skibinski, Ph.D., director of research programs at MJFF . “ We look forward to seeing the results of Lario’s research on CaV2.3 as a novel disease-modifying approach for Parkinson’s .” Richard Wade-Martins, MA, DPhil, Professor of Molecular Neuroscience, University of Oxford, and head of the Oxford Parkinson’s Disease Centre, said: “ I am excited to partner with the team at Lario Therapeutics – having grant funding from MJFF is a testament to the impact this study aims to bring to patients. Our research centre works to understand the development of Parkinson’s, with the ultimate aim of targeting the molecular mechanisms of disease, to prevent disease onset or to delay progression. We see great potential in the CaV2.3 programme and are very happy to collaborate to study patient stem cell-derived neuronal models as part of the research.” For more information about Lario Therapeutics' pipeline please visit https://www.lariotx.com/pipeline .

Researchers have identified a potential treatment target for a genetic type of epilepsy.   Researchers at the Francis Crick Institute, UCL and MSD have identified a potential treatment target for a genetic type of epilepsy. Developmental and epileptic encephalopathies are rare types of epilepsy which start in early childhood. One of the most common types of genetic epilepsy, CDKL5 deficiency disorder (CDD), causes seizures and impaired development. Children are currently treated with generic antiepileptic drugs, as there aren't yet any disease-targeting medications for this disorder. CDD involves losing the function of a gene producing the CDKL5 enzyme, which phosphorylates proteins, meaning it adds an extra phosphate molecule to alter their function. Until now, researchers have not been sure how genetic mutations in CDKL5 cause CDD. Through their research, published today in Nature Communications, the researchers examined mice which lacked the Cdkl5 gene, and used a technique called phosphoproteomics to scan for proteins which are a target for the CDKL5 enzyme. They identified a calcium channel, Cav2.3, as a target. Cav2.3 allows calcium to enter nerve cells, exciting the cell and allowing it to pass on electrical signals. This is needed for the nervous system to function properly, but too much calcium coming into cells can result in overexcitability and seizures. The researchers then recorded from the calcium channels to see what was happening when they were not being phosphorylated by CDKL5. The channels were able to open, but were taking a lot longer to close, leading to larger and more prolonged currents flowing through them. This implies that CDKL5 is needed to limit calcium entry into cells. The researchers also used nerve cells derived from stem cells taken from people with CDD, again observing that phosphorylation of Cav2.3 was reduced. This suggests that Cav2.3 function is potentially altered in humans as well as mice. Mutations in Cav2.3 that enhance channel activity are already known to cause severe early onset epilepsy in a related condition called DEE69, which shares a lot of the same symptoms of CDD. These results suggest that Cav2.3 overactivity is a common feature of both disorders, and that inhibiting Cav2.3 could help with symptoms like seizures. Sila Ultanir, Senior Group Leader of the Kinases and Brain Development Laboratory at the Crick, said: "At the moment, there's a clear need for drugs which specifically target the biological nature of CDD. We've made a molecular link between CDKL5 and Cav2.3, mutations in which produce similar disorders. Inhibiting Cav2.3 could be a route for trials of future targeted treatments." Marisol Sampedro-Castañeda, postdoctoral researcher at the Crick, and first author, said: "Our research highlights for the first time a CDKL5 target with a link to neuronal excitability. There's scattered evidence that this calcium channel could be involved in other types of epilepsy too, so we believe that Cav2.3 inhibitors could eventually be tested more widely. "Our findings have implications for a large group of people, from the families affected by these conditions to researchers working in the rare epilepsy field." This research was funded by MSD and the Loulou Foundation, a private foundation dedicated to the development of therapeutics and eventual cures for CDD. Jill Richardson, Executive Director and Head of Neuroscience Biology at MSD, said: "MSD is proud of this innovative research resulting from a collaboration with researchers at the Crick and UCL. We have collectively furthered our scientific understanding of the biological targets associated with the aetiologies of Developmental Epileptic Encephalopathies -- an understanding we hope will contribute toward scientific progress in this important area of high, unmet medical need." The researchers are now working with Lario Therapeutics, a recently launched biotech company which is seeking to develop first-in-class CaV2.3 inhibitors as precision medicines to treat CDD and related neurodevelopmental syndromes.

无论是自由形式，还是与眼镜蛇毒素calciseptine、氨氯地平，胺碘酮与索非布韦结合，Cav1.2通道都呈现出一致的失活构象。在解析多种药物调控Cav1.2的作用机制的过程中，该研究获得三个重要的 颜宁教授联合武汉大学药学院高帅教授、北京大学宋晨研究员，在 Cell 期刊发表了题为：Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine 的研究论文。 该研究揭示了自由状态、多种药物结合、多肽毒素结合的钙离子通道Cav1.2的高分辨结构。 无论是自由形式，还是与眼镜蛇毒素calciseptine、氨氯地平，胺碘酮与索非布韦结合，Cav1.2通道都呈现出一致的失活构象。在解析多种药物调控Cav1.2的作用机制的过程中，该研究获得三个重要的非预期发现： 第一，尽管Cav1.2 与Cav1.3同属于L型钙离子通道，在功能及序列上高度同源，但Cav1.2在部分结构特性上更接近于神经钙离子通道Cav2.2/Cav2.3。具体而言，Cav1.2，Cav2.2，Cav2.3的电压感受结构域II （VSDII）处于down构象；Cav1.1，Cav1.3的VSDII则处于up构象； 第二，该研究解析了眼镜蛇毒素calciseptine致死的分子机制，颠覆了以往对动物毒素调控离子通道功能的认知。经典的动物毒素结合模式一般是通过结合在离子孔结构域阻碍离子运输，或者结合在电压感受结构域变构调控离子通道功能。在本工作中，Calciseptine结合在Cav1.2离子孔外周的肩膀区域，这种崭新的结合模式稳定了Cav1.2通道失活状态的构象，导致蛋白功能抑制。毒素及蛋白定点突变电生理研究进一步验证了该结合模式； 第三，该研究在解析胃肠道解痉剂匹维溴铵调控机制时，发现了Cav1.2通道的全新失活构象。在该构象中，VSDII呈现up状态，离子孔扩大，选择性滤器（SF）构象改变。与此同时，重复单元III的S4-S5与S5两个α螺旋元件融合成单个螺旋，导致细胞内孔（Intracellular gate）变宽。除匹维溴铵外，氨氯地平等其他药物分子不能结合该构象。通过分子动力学模拟证实，这个孔道结构域变大的构象仍不能通透钙离子，通道蛋白处于失活状态。 武汉大学药学院高帅教授、深圳医学科学院颜宁教授、北京大学宋晨研究员为该论文共同通讯作者。武汉大学药学院高帅教授、姚霞教授、清华大学陈姣凤博士为论文共同第一作者。武汉大学药学院为文章第一完成单位。清华大学化学系刘磊教授、圣约翰大学于勇教授为该工作提供了关键技术支持。 这是高帅教授在Nature（2021）、Cell Research（2022）、Cell（2022）、Nature Communications（2022）杂志发表钙离子通道镇痛药物齐考诺肽、抗晕动症药物桂利嗪，丙肝神药索非布韦副反应作用机制后，在该领域的又一系统性、突破性进展，为钙离子通道蛋白新型靶向药物研发奠定了重要的理论基础。