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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：
7392221
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 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7392221
关键词：
Acute Animal Model Animals Anxiety Applications Grants Attention Autistic Disorder Basic Science Brain Brain Diseases Chemicals Chronic Clinical 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 Guanosine Monophosphate 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 Personal Satisfaction 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 Standards of Weights and Measures Symptoms Testing Therapeutic Time Toxic effect Toxicology Translating United States Food and Drug Administration absorption autistic behaviour cognitive function day design drug development 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）：该项目的长期目标是将人类大脑发育障碍的遗传发现转化为对这些疾病的有效治疗。人类遗传学研究表明，一种常见的精神发育迟滞形式称为脆性X综合征（FXS），是单一基因FMR1突变的结果，FMR1阻止了单一蛋白质（FMRP）的表达。缺乏FMRP的脑发育与显著的发病率相关，包括认知功能受损、注意力缺陷和多动、焦虑、强迫和自闭症行为。对于脆性X综合征没有有效的治疗方法。理解脆性X突变对大脑发育和功能的影响，已经通过产生模拟脆性X综合征的基因工程动物而得到了促进。过去十年来在这些动物模型中积累的科学证据表明，脆性X的症状反映了mGluR5（一种代谢型谷氨酸受体）下游的蛋白质合成过多。基因敲低mGluR5表达可以挽救Fmr1敲除小鼠的多种表型。此外，急性和慢性治疗脆性X小鼠和苍蝇模型与mGluR5拮抗剂在体内保护突变动物癫痫发作，认知功能受损，改变大脑发育。因此，证据清楚地表明mGluR5是开发治疗脆性X染色体的药物的有效靶点。我们提案的目的是推进默克公司许可的mGluR5拮抗剂进入人体临床试验。海滨治疗公司已经从默克公司获得了几种高选择性、强效和口服的mGluR5拮抗剂的许可，我们打算开发先导化合物STX 107，用于治疗FXS和潜在的自闭症。我们在这笔赠款中要求将这些引人注目的基础科学发现转化为临床研究所需的资金，目的是为FXS和其他大脑发育障碍提供有意义的治疗方法。我们将通过推进我们的先导化合物STX107，通过必要的临床前研究来实现这一目标，以满足FDA的要求，开启研究性新药申请并在人体中进行初步测试。这些研究提供了基础，使我们能够测试我们的假设，即mGluR5拮抗剂可以有效治疗FXS和其他大脑发育障碍，包括自闭症。相关性：我们的研究第一次为脆性X综合征的药物治疗提供了一个合理的科学依据，并可能为自闭症等其他大脑发育障碍提供药物治疗。