Development of mGluR5 Antagonists to Treat Fragile X Syndrome and 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基因发现转化为有效的治疗方法。人类基因研究表明，一种被称为脆性X染色体综合征（FXS）的常见智力迟钝形式是单个基因FMR1突变的结果，该基因阻止了单个蛋白质（FMRP）的表达。缺乏FMRP的大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、强迫症和自闭症行为。目前还没有有效的治疗脆性X染色体综合征的方法。了解脆性X突变对大脑发育和功能的影响，已经通过一代遗传工程动物来模拟脆性X综合征。过去十年在这些动物模型中积累的科学证据表明，脆性X的症状反映了代谢性谷氨酸受体mGluR5下游过度的蛋白质合成。基因敲低mGluR5表达可以挽救Fmr1敲除小鼠的多种表型。此外，体内用mGluR5拮抗剂急性和慢性治疗脆性X小鼠和果蝇模型，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的药物的有效靶点。我们提议的目的是推进默克许可的mGluR5拮抗剂进入人体临床试验。Seaside Therapeutics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STX107，用于治疗FXS和潜在的自闭症。我们在此拨款中请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。我们将推进我们的先导化合物STX107，通过必要的临床前研究，以满足FDA的要求，打开新药研究申请并进行初步人体试验，从而实现这一目标。这些研究提供了基础，使我们能够验证我们的假设，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：我们的研究首次为脆性X染色体综合征的药物治疗提供了可靠的科学依据，并可能为其他大脑发育障碍（如自闭症）的治疗提供依据。

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.