Development of mGlu7 receptor allosteric modulators for neurological and psychiatric disorders

开发治疗神经和精神疾病的 mGlu7 受体变构调节剂

基本信息

批准号：
10266776
负责人：
CRAIG LINDSLEY
金额：
$ 69.51万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-21 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10266776
关键词：
Agreement Alleles Amygdaloid structure Anxiety Apnea Architecture Attention deficit hyperactivity disorder Biological Markers Brain Brain region Characteristics Chemicals Chemosensitization Clinic Clinical Clinical Paths Cognitive Cognitive deficits Coupled DNA Sequence Alteration Data Development Diagnosis Disease Dose Drug Kinetics Drug Targeting Electroencephalogram Engineering Epilepsy Exhibits Expression Profiling Frequencies Future G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Genes Genetic Diseases Glutamates Goals Hippocampus (Brain)Human Intellectual functioning disability Investigational Drugs Knock-out Knockout Mice Link Location Long-Term Potentiation Mental Depression Mental disorders Metabolism Metabotropic Glutamate Receptors Methyl-CpG-Binding Protein 2 Modeling Motor Mus Mutation Nature Neurodevelopmental Disorder Neurologic Outcome Measure Pathogenicity Patients Pattern Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phenotype Point Mutation Population Pre-Clinical Model Proteins REM Sleep Reporting Rett Syndrome Rodent Role Safety Sampling Schizophrenia Seizures Single Nucleotide Polymorphism Sleep Stereotyped Behavior Synaptic plasticity Syndrome Testing Therapeutic Tissues Transcriptional Regulation Treatment Efficacy Validation autism spectrum disorder autistic clinical Diagnosis clinical development clinical heterogeneity clinically translatable cohort common symptom drug development efficacy testing epigenetic regulation gamma-Aminobutyric Acid in vivo loss of function mutation metabotropic glutamate receptor 7 mouse development mouse model mutant mutant mouse model nervous system disorder neurotransmitter release novel therapeutic intervention patient subsets positive allosteric modulator pre-clinical presynaptic programs receptor research clinical testing respiratory response scaffold sleep abnormalities small molecule social stereotypy targeted treatment tool

项目摘要

PROJECT SUMMARY Metabotropic glutamate receptor 7 (mGlu7) regulates presynaptic neurotransmitter release widely throughout the CNS and is required for the induction of long-term potentiation (LTP) in the hippocampus and amygdala, suggesting a central role in synaptic plasticity. Recently, primary mutations in the GRM7 gene have been linked to intellectual disability, stereotypies, and seizures, symptoms common in neurodevelopmental disorders. Additionally, we have found that mGlu7 protein levels are significantly reduced in the brains of patients clinically diagnosed with the neurodevelopmental disorder, Rett syndrome (RTT). Loss-of-function mutations in Methyl CpG Binding Protein 2 (MECP2), an epigenetic regulation of transcription, are the major cause of RTT, which is a disease resulting in the development of stereotyped behaviors, motor delays, anxiety, cognitive deficits, autistic features, seizures, and apneas. Consistent with reductions in mGlu7 in RTT patients and model mice, potentiating mGlu7 activity with small molecule positive allosteric modulators (PAMs) corrects multiple synaptic plasticity, cognitive, social, and respiratory phenotypes in mice with an Mecp2 knockout (KO) allele. These early studies employed a compound that was not selective for mGlu7 versus several other metabotropic glutamate receptors. We have recently optimized VU6027459, a highly selectivity mGlu7 tool that exhibits suitable pharmacokinetic parameters for in vivo rodent use. Using VU6027459, we have further validated a role for mGlu7 potentiation in reversing abnormal RTT phenotypes. We propose to use the monogenetic disorder of RTT, in tandem with a drug development campaign, as a clinical entry path for the development of mGlu7 PAMs; it is anticipated that future studies could then expand into alternate indications, such as primary epilepsies or schizophrenia. Our previous RTT studies have focused on patients and mice with an MECP2/Mecp2 allele that is a functional null. A large proportion of RTT patients, however, have single point mutations in the MECP2 gene, and our preliminary data suggest that there are differences in mGlu7 expression levels in human RTT tissue that correlate with specific mutations. This indicates that therapeutics for efficacy testing in this disease require preclinical validation in various mouse models that reflect this clinical heterogeneity. Using an expanded clinical sample set and mice modeling different mutations, we will test the hypothesis that mGlu7 levels may be differentially impacted in the context of distinct MECP2 mutations and determine if specific mutations underlie disease states most likely to exhibit efficacious and safe responses to mGlu7 PAMs or if mGlu7 PAMs will have utility across the entire mutation spectrum. Finally, we will perform biomarker studies that build upon our findings that Mecp2- deficient mice exhibit EEG spectral changes and reductions in REM sleep across the disease course. These findings mirror sleep abnormalities seen in RTT patients, suggesting that EEG represents a clinically translatable and noninvasive biomarker for the program.

项目摘要代谢性谷氨酸受体7（MGLU7）调节整个整个过程中突触前神经递质的释放中枢神经系统是在海马和杏仁核中诱导长期增强（LTP）所必需的提示在突触可塑性中起着核心作用。最近，GRM7基因中的主要突变已连接对于智力残疾，刻板印象和癫痫发作，在神经发育障碍中常见的症状。此外，我们发现临床患者的大脑中MGLU7蛋白水平显着降低被诊断为神经发育障碍，RETT综合征（RTT）。甲基的功能丧失突变 CpG结合蛋白2（MECP2）是转录的表观遗传调节，是RTT的主要原因，这是一个疾病导致陈规定型行为，运动延迟，焦虑，认知缺陷，自闭症的发展功能，癫痫发作和呼吸暂停。与RTT患者和模型小鼠的MGLU7减少一致，增强小分子阳性变构调节剂（PAM）的MGLU7活性纠正了多种突触可塑性， MECP2敲除（KO）等位基因的小鼠的认知，社交和呼吸表型。这些早期研究与其他几种代谢型谷氨酸受体相比，使用了对MGLU7的选择性的化合物。我们最近优化了VU6027459，这是一种表现出合适的药代动力学的高度选择性mglu7工具体内啮齿动物使用的参数。使用VU6027459，我们进一步验证了MGLU7增强作用逆转异常的RTT表型。我们建议将RTT的单基因疾病与A一起使用药物开发运动，作为MGLU7 PAM开发的临床进入道路；预计然后，未来的研究可能会扩展为替代指示，例如原发性癫痫或精神分裂症。我们以前的RTT研究集中在患者和MECP2/MECP2等位基因的患者和小鼠上无效的。但是，很大一部分RTT患者在MECP2基因中具有单点突变，我们初步数据表明，人类RTT组织中MGLU7表达水平存在差异具有特定的突变。这表明该疾病功效测试的治疗剂需要临床前反映这种临床异质性的各种小鼠模型的验证。使用扩展的临床样本集和对不同突变进行建模的小鼠，我们将检验以下假设：MGLU7水平可能是差异的在不同的MECP2突变的背景下受到影响，并确定特定突变是否是疾病状态的基础最有可能对MGLU7 PAM表现出有效且安全的反应，或者MGLU7 PAM是否会在整个整个突变光谱。最后，我们将进行生物标志物研究，以MECP2-的发现为基础缺乏小鼠在整个疾病过程中表现出EEG光谱的变化和REM睡眠的减少。这些发现镜面睡眠异常在RTT患者中，表明脑电图代表临床上可翻译的和该计划的无创生物标志物。