Development of mGluR5 Antagonists to Treat Fragile X Syndrome and Autism

描述(申请人提供)：该项目的长期目标是将人类大脑发育障碍的基因发现转化为治疗这些疾病的有效方法。人类遗传学研究表明，一种常见的精神发育迟滞被称为脆性X综合征(FXS)，它是单一基因FMR1突变的结果，该基因阻止单一蛋白(FMRP)的表达。缺乏FMRP的大脑发育与显著的发病率有关，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。目前还没有有效的治疗脆性X综合征的方法。通过建立脆性X综合征模型的基因工程动物的产生，有助于了解脆性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下游蛋白质的过度合成，mGluR5是一种代谢性谷氨酸受体。基因敲除mGluR5表达可以挽救Fmr1基因敲除小鼠的多种表型。此外，在体内用mGluR5拮抗剂急性和长期治疗脆性X小鼠和苍蝇模型可以保护突变动物免受癫痫发作、认知功能损害和大脑发育的改变。因此，证据清楚地表明，mGluR5是开发治疗脆性X的药物的有效靶点。我们提议的目的是推动从默克公司获得许可的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度选择性、有效和口服使用的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，以将这些引人注目的基础科学发现转化为临床研究，目的是为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，通过必要的临床前研究来实现这一点，以满足FDA的要求，开启研究性新药申请并在人体上进行初步测试。这些研究提供了基础，使我们能够检验我们的假设，即mGluR5拮抗剂可以有效地治疗FXS和包括自闭症在内的其他大脑发育障碍。相关性：我们的研究首次提出了对脆性X综合征以及其他大脑发育障碍(如自闭症)进行药物治疗的合理科学依据。

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.