Development of mGluR5 Antagonists to Treat Fragile X Syndrome and Autism

开发 mGluR5 拮抗剂治疗脆性 X 综合征和自闭症

基本信息

批准号：
7635745
负责人：
Randall L Carpenter
金额：
$ 106.81万
依托单位：
SEASIDE THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7635745
关键词：
Acute Animal Model Animals Anxiety Applications Grants Attention Autistic Disorder Basic Science Brain Brain Diseases Chemicals Chronic Clinical Research Clinical Trials Development Disease Dose Drug Kinetics Engineering Excretory function FMR1 FMR1 Gene Foundations Fragile X Syndrome Funding Future Generations Genetic Goals Grant Guidelines Human Human Genetics Hyperactive behavior Investigational Drugs Investigational New Drug Application Knockout Mice Lead Licensing Mental Retardation Metabolism Metabotropic Glutamate Receptors Modeling Morbidity - disease rate Mus Mutation Orphan Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Phase II Clinical Trials Phenotype Process Protein Biosynthesis Proteins Rattus Research Research Personnel Rodent Safety Screening procedure Seizures Series Symptoms Testing Therapeutic Time Toxic effect Toxicology Translating United States Food and Drug Administration absorption autistic behaviour clinical practice cognitive function design drug development effective therapy fly genotoxicity improved in vivo knockout animal mutant pre-clinical preclinical study prevent sound theories volunteer

项目摘要

DESCRIPTION (provided by applicant): The long-term aim of this project is to translate genetic discoveries in humans with disorders of brain development into effective treatments for humans with these disorders. Human genetic studies have revealed that a common form of mental retardation known as fragile X syndrome (FXS) is a consequence of mutations in a single gene, FMR1, which prevents expression of a single protein (FMRP). Brain developmental in the absence of FMRP is associated with significant morbidity including impaired cognitive function, attention deficit and hyperactivity, anxiety, obsessive-compulsive and autistic behaviors. There are no effective treatments for fragile X syndrome. Understanding the effects of the fragile X mutation on brain development and function has been facilitated by generation of genetically engineered animals that model fragile X syndrome. The accumulated scientific evidence in these animal models over the last decade suggests that the symptoms of fragile X reflect excessive protein synthesis downstream of mGluR5, a metabotropic glutamate receptor. Genetic knockdown of mGluR5 expression can rescue multiple phenotypes in Fmr1 knockout mice. Moreover, acute and chronic treatment of fragile X mouse and fly models with mGluR5 antagonists in vivo has protected mutant animals from seizures, impaired cognitive function, and altered brain development. Thus, the evidence clearly indicates that mGluR5 is a valid target for development of drugs to treat fragile X. The aim of our proposal is to advance an mGluR5 antagonist licensed from Merck into human clinical trials. Seaside Therapeutics has licensed from Merck several highly selective, potent and orally available mGluR5 antagonists and we intend to develop the lead compound, STX107, to treat FXS and, potentially autism. We request in this grant the funds needed to translate these compelling basic science discoveries into clinical research with the goal of providing meaningful treatments for FXS and other disorders of brain development. We will accomplish this by advancing our lead compound, STX107, through the preclinical studies necessary to fulfill FDA requirements to open an Investigational New Drug application and perform initial testing in humans. These studies provide the foundation that will allow us to test our hypothesis that mGluR5 antagonists can be an effective treatment of FXS and other disorders of brain development including autism. Relevance: Our research suggests for the first time a sound scientific rationale for pharmacologic treatment of fragile X syndrome and, potentially, other disorders of brain development such as autism.

描述（由申请人提供）：该项目的长期目的是将脑发育障碍的人类的遗传发现转化为对患有这些疾病的人类的有效治疗。人类遗传研究表明，一种称为脆弱X综合征（FXS）的常见智力迟缓形式是单个基因FMR1突变的结果，该基因阻止了单个蛋白质（FMRP）的表达。在没有FMRP的情况下，脑发育与明显的发病率有关，包括认知功能受损，注意力缺陷和多动症，焦虑，强迫症和自闭症行为。易碎X综合征没有有效的治疗方法。通过对脆弱X综合征建模的基因工程动物的产生，了解脆弱X突变对脑发育和功能的影响。在过去十年中，这些动物模型中积累的科学证据表明，脆弱X的症状反映了MGLUR5下游的过度蛋白质合成，一种代谢性谷氨酸受体。 MGLUR5表达的遗传敲低可以挽救FMR1基因敲除小鼠的多种表型。此外，用MGLUR5拮抗剂在体内对脆弱的X小鼠和苍蝇模型的急性和慢性治疗使突变动物免受癫痫发作，认知功能受损并改变了脑发育。因此，证据清楚地表明，MGLUR5是用于处理脆弱X的药物开发的有效靶标。我们的提议的目的是将许可的MGLUR5拮抗剂从默克公司授权到人类临床试验。 Seaside Therapeutics已从默克（Merck）获得了几种高度选择性，有效和口服的MGLUR5拮抗剂的许可，我们打算开发铅化合物STX107，以治疗FXS和潜在的自闭症。我们在这笔赠款中要求将这些引人入胜的基础科学发现转化为临床研究所需的资金，目的是为FXS和其他大脑发育的其他疾病提供有意义的治疗方法。我们将通过满足FDA要求开放研究新药应用并在人类中进行初始测试所需的临床前研究来实现这一目标。这些研究为我们的假设提供了一个基础，即MGLUR5拮抗剂可以成为FXS和其他大脑发育障碍（包括自闭症）的有效治疗方法。相关性：我们的研究首次提出了对脆弱X综合征的药理治疗以及可能的其他脑发育障碍（例如自闭症）的良好科学原理。