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：
10093390
负责人：
CRAIG LINDSLEY
金额：
$ 74.11万
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/10093390
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.

项目概要代谢型谷氨酸受体 7 (mGlu7) 广泛调节突触前神经递质的释放中枢神经系统，是诱导海马体和杏仁核长时程增强 (LTP) 所必需的，表明在突触可塑性中起着核心作用。最近，GRM7 基因的主要突变已被证实智力障碍、刻板印象和癫痫发作，这些都是神经发育障碍的常见症状。此外，我们在临床上发现患者大脑中的 mGlu7 蛋白水平显着降低被诊断患有神经发育障碍，雷特综合征（RTT）。甲基功能缺失突变 CpG 结合蛋白 2 (MECP2) 是转录的表观遗传调控，是 RTT 的主要原因，RTT 是一种导致刻板行为、运动迟缓、焦虑、认知缺陷、自闭症的疾病特征、癫痫发作和呼吸暂停。与 RTT 患者和模型小鼠中 mGlu7 的减少一致，增强 mGlu7 活性与小分子正变构调节剂 (PAM) 可以纠正多种突触可塑性， Mecp2 敲除 (KO) 等位基因小鼠的认知、社交和呼吸表型。这些早期研究使用了一种与其他几种代谢型谷氨酸受体相比对 mGlu7 没有选择性的化合物。我们最近优化了 VU6027459，这是一种高选择性 mGlu7 工具，具有合适的药代动力学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 RTT 表型。我们建议将 RTT 单基因疾病与药物开发活动，作为 mGlu7 PAM 开发的临床进入途径；预计未来的研究可以扩展到其他适应症，例如原发性癫痫或精神分裂症。我们之前的 RTT 研究重点关注具有功能性 MECP2/Mecp2 等位基因的患者和小鼠。无效的。然而，很大一部分 RTT 患者的 MECP2 基因存在单点突变，我们的研究初步数据表明，人类 RTT 组织中 mGlu7 表达水平存在差异，这与具有特定的突变。这表明对该疾病的疗效测试的治疗方法需要临床前在反映这种临床异质性的各种小鼠模型中进行了验证。使用扩展的临床样本集和小鼠模型不同的突变，我们将测试 mGlu7 水平可能存在差异的假设在不同 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 表现出有效和安全的反应，或者 mGlu7 PAM 是否将在整个领域发挥作用整个突变谱。最后，我们将基于 Mecp2- 的发现进行生物标志物研究缺陷小鼠在整个病程中表现出脑电图频谱变化和快速眼动睡眠减少。这些研究结果反映了 RTT 患者的睡眠异常，表明脑电图代表了临床上可转化的睡眠异常。以及该计划的非侵入性生物标志物。