Recent research progress in the field of central nervous system diseases (06.22)
Recent research progress in the field of central nervous system diseases (06.22) June 22, 2018 Source: WuXi PharmaTech 1. Parkinson's disease mechanism is further revealed Recently, researchers from the Baylor College of Medicine and the Texas Children's Hospital in Texas have further revealed the mechanism of early onset PD, the key Ceramide dysregulation, the related paper published in the "cell" magazine "Cell Metabolism". â–² Image source: 123RF Parkinson's disease is a neurodegenerative disease that affects dopaminergic neurons in the brain, including limb tremors, slowing of movement, muscle stiffness, impaired posture and balance, loss of voluntary motor function, and speech changes. . The disease affects more than 10 million people worldwide. Although there is currently no cure for Parkinson's disease, there are drugs that can slow its progression. The author/communication contact, Dr. Hugo J. Bellen, a professor of molecular and human genetics and neuroscience at Baylor College of Medicine and a researcher at the Howard Hughes Medical Institute, noted that many genes are known to be Parkinson Related to diseases, such as the PLA2G6 (PARK14) gene encoding phospholipase PLA2G6, which often causes neurodegenerative diseases in humans, including autosomal recessive axonal dystrophy and early-onset Parkinson's disease, but currently There is not much understanding of how these genes cause Parkinson's disease. The new findings suggest that the key to linking Parkinson's disease-associated genes to cellular defects is ceramide, a family of intracellular lipid molecules. Tests have shown that deletion of phospholipase PLA2G6 or a decrease in Vps35 may result in disruption of the function of the retrosome. Retromer is a protein complex composed of protein dimers (SNX1, SNX2, SNX5, SNX6) and vacuolar protein sorting (Vps) trimers (Vps26, Vps29, Vps35). In the Drosophila model, deletion of the PLA2G6 homolog iPLA2-VIA reduces the lifespan of Drosophila, impairs synaptic transmission and causes neurodegeneration. Phospholipases typically hydrolyze glycerophospholipids, but the loss of iPLA2-VIA does not affect the phospholipid composition of brain tissue, but rather causes an increase in ceramide. Reducing ceramide with drugs such as myriocin or desipramine can alleviate lysosomal stress and inhibit neurodegeneration. iPLA2-VIA binds to retromer's Vps35 and Vps26 subunits to enhance its function and promote protein and lipid recycling. If iPLA2-VIA is damaged, it will damage the retromer function, resulting in ceramide accumulation. This causes a positive feedback loop that affects membrane fluidity and neuronal function. Similar defects were observed in models that removed vps26 or vps35 or overexpressed alpha-synuclein, suggesting that these defects may be a common mechanism in Parkinson's disease. 2. Genentech anti-MS new drug significantly delays the onset of symptoms of disability in patients Recently, Roche's Genentech announced that it will announce the latest clinical phase 3 trial data of OCREVUS (ocrelizumab). The results showed that OCRENUS significantly delayed the time required for patients with primary progressive multiple sclerosis (PPMS) to be wheelchair-assisted. Multiple sclerosis (MS) is an autoimmune disease caused by the body's immune system attacking the myelin sheath that protects nerve fibers. As the damage of the myelin sheath becomes more and more serious, the ability of the patient's nerve fibers to transmit information gradually decreases, and some patients may not be able to walk independently. Because oligodendrocytes in the central nervous system can repair myelin, many MS patients have a remission period. However, about 15% of MS patients are PPMS. These patients usually have no remission period, and their symptoms continue to increase because the speed of disability is greatly accelerated. Ocrelizumab, developed by Genentech, is a humanized monoclonal antibody targeting CD20 that causes CD20+ B lymphocyte death by binding to CD20. CD20+ B lymphocytes play a key role in causing myelin and nerve damage. Ocrelizumab binds to CD20 expressed on the surface of B cells, but it does not bind to stem cells or plasma cells, so it does not affect other important functions of the immune system. Ocrelizumab has been approved by the US FDA for the treatment of patients with MS and PPMS. In a clinical randomized double-blind trial called ORATORIO, 732 PPMS patients were treated with ocrelizumab or placebo. The trial data showed that ocrelizumab was able to reduce the patient's disability to 46% (see risk value 6.2% vs. 9.8%, p=0.022) compared with placebo. Using these data, the researchers estimated that patients who received ocrelizumab required an average of 19.2 years to require a wheelchair, while patients who received placebo required an average of 12.1 years to require a wheelchair. Therefore, ocrelizumab therapy can delay the patient's need for a wheelchair for 7 years. 3. FDA support, breakthrough new drugs for depression will speed up research and development Recently, Sage Therapeutics announced that it will accelerate the development of its new drug SAGE-217 after a breakthrough therapy meeting with the US FDA. The program is designed to support the approval of SAGE-217 for the treatment of major depressive disorder (MDD) and postpartum depression (PPD) in the United States. MDD is a common but serious emotional disorder in which patients exhibit depression or loss of fun in their daily activities and create barriers to social, professional, educational or other important activities. It is estimated that about 16 million people in the United States suffer from these diseases each year. Although antidepressants are widely used in treatment, large-scale studies have proven that patients need additional treatment. While PPD is a common birth-related complication, the effects on some women usually begin within three months of pregnancy or within a few months after delivery. Postpartum depression can have devastating consequences for women and families, including significant dysfunction, depression, loss of interest in newborns, and associated depressive symptoms. However, there is currently no FDA-approved postpartum depression therapy, and there are significant medical needs in this area that are not being met. SAGE-217 is the next generation of positive allosteric modulators and is expected to bring therapeutic hope to patients with MDD and PPD. It is optimized for the selectivity of synaptic and extrasynaptic GABA receptors, as well as the pharmacokinetic profile of daily oral administration. The GABA system is the main inhibitory signaling pathway in the brain and central nervous system, and is important for regulating central nervous system function. The drug was approved by the FDA in February this year for the treatment of MDD. Sage's rapid development program for SAGE-217 includes a single additional placebo-controlled phase 3 critical trial in MDD patients and a placebo-controlled trial (now designated as a key trial) in women with PPD. Both clinical trials were designed to assess the effect of SAGE-217 episodic dosing or short-term treatment on reducing depressive symptoms compared with placebo. An open-label study will assess the efficacy of sporadic treatment for new or recurrent MDD and provide additional safety data. 4. Significantly reduce the number of seizure days, migraine new drug phase 3 clinical results are positive Allergan has announced that its research drug Atogepant has achieved positive results in clinical phase 2b/3 trials, reaching the primary study endpoint in all dose regimens and significantly reducing migraine in a statistically significant manner. The number of intermittent monthly episodes of the patient. Atogepant is a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist. Migraine is a chronic disease with neurological symptoms such as headache, sensitivity to light, sound, and nausea. These symptoms are usually incurable and can last for more than a day, seriously hampering the patient's normal life function. It even caused the work to be completely stagnant. Migraine is very common, affecting about one-seventh of the world's population (affecting 12% of the US population, including children) and is associated with significant disability, leading to social and economic burdens. Patients with intermittent migraine usually have 4-14 days of headache per month. Current care standards for acute treatment of migraine are not optimal for many patients, and there are limitations such as limited efficacy, poor tolerance, or contraindications. Patients may experience uncontrolled migraine repeatedly, leading to increased drug overuse and increased risk of disease progression. Compared with current standards of care, new migraine treatments are needed to increase effectiveness, reduce risk, and benefit more patients. CGRP and its receptor are expressed in the nervous system region associated with the pathophysiology of migraine. CGRP receptor antagonism is a new mechanism of action in the acute treatment of migraine, which is significantly different from the existing triptans (serotonin 1B / 1D agonist) and opioids. Atogepant is the second CGRP receptor antagonist developed by Ai Jian following Ubrogepant, which can significantly reduce the number of days of acute migraine attacks. Ai Jian believes that CGRP antagonist drugs can complement the company's Botox, which can be used to treat chronic migraine. The CGP-MD-01 clinical trial was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study of phase 2b/3 in the United States for a period of 12 weeks. The trial included a random 4-week screening/baseline period, a 12-week double-blind treatment period, and a 4-week safety follow-up period. 834 subjects aged between 18 and 75 years (mean 40.1 years), history of migraine (with or without aura) for at least 1 year, and baselines were screened 3 months and 28 days prior to the first visit There were an average of 4 to 14 migraine/most likely migraine (MPM) episodes per month during the period. A total of 82% of patients completed the study, and the discontinuation rate was similar in all treatment groups. The results of the trial showed that Atogepant reached the primary endpoint in all dose regimens. Efficacy analysis was based on a population of 795 modified intention-to-treat (mITT) patients. The primary efficacy endpoint was the change in mean monthly MPM episodes from baseline over the 12-week treatment period. In addition, Atogepant was well tolerated and liver safety was similar to the placebo group. Reference materials: [1] As Treatments Await FDA Ruling, Researchers Discover 'Key Players' in Early-Onset Parkinson's Disease [2] Genentech Announces New OCREVUS (Ocrelizumab) Data on Long-Term Disability Benefits in Primary Progressive Multiple Sclerosis and Initiation of Two Global Studies in Progressive MS [3] Sage Announces Pivotal Phase 3 Trial Status for SAGE-217 in Major Depressive Disorder and Postpartum Depression based on FDA Breakthrough Therapy Meeting [4] Allergan's Atogepant Hits the Mark in Phase IIb/III Episodic Migraine Trial Original Title: Recent Research Progress in the Field of Central Nervous System Diseases (No. 56) Automatic Cable Reel,Automatic Water Hose Reel,Industrial Water Hose Reel,Automatic Garden Hose Reel NINGBO QIKAI ENVIRONMENTAL TECHNOLOGY CO.,LTD , https://www.water-hose-reel.com
