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：
7261528
负责人：
Randall L Carpenter
金额：
$ 117.73万
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/7261528
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患有大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。人类遗传学研究表明，一种常见的精神发育迟滞（称为脆性 X 综合征 (FXS)）是单个基因 FMR1 突变的结果，该基因阻止单个蛋白质 (FMRP) 的表达。在缺乏 FMRP 的情况下，大脑发育与显着的发病率相关，包括认知功能受损、注意力缺陷和多动、焦虑、强迫症和自闭症行为。脆性 X 综合征没有有效的治疗方法。模拟脆性 X 综合征的基因工程动物的产生促进了人们了解脆性 X 突变对大脑发育和功能的影响。过去十年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）下游蛋白质合成过多。 mGluR5 表达的基因敲除可以挽救 Fmr1 敲除小鼠的多种表型。此外，用 mGluR5 拮抗剂对脆性 X 小鼠和果蝇模型进行体内急性和慢性治疗，可以保护突变动物免受癫痫发作、认知功能受损和大脑发育改变。因此，证据清楚地表明 mGluR5 是开发治疗脆性 X 细胞药物的有效靶点。我们提案的目的是将默克公司许可的 mGluR5 拮抗剂推进人体临床试验。 Seaside Therapeutics 已从默克公司获得了几种高选择性、强效、口服的 mGluR5 拮抗剂的许可，我们打算开发先导化合物 STX107，用于治疗 FXS 和潜在的自闭症。我们在这笔赠款中请求所需的资金，将这些引人注目的基础科学发现转化为临床研究，目标是为 FXS 和其他大脑发育障碍提供有意义的治疗。我们将通过推进我们的先导化合物 STX107 来实现这一目标，通过必要的临床前研究来满足 FDA 开放研究性新药申请并在人体中进行初步测试的要求。这些研究为我们检验我们的假设奠定了基础，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：我们的研究首次为脆性 X 综合征以及自闭症等其他大脑发育障碍的药物治疗提供了合理的科学依据。