Neuroactive Steroid GABAA Receptor Positive Modulators for Fragile X Syndrome

描述(申请人提供)：虽然脆性X综合征的主要特征是认知功能障碍，但绝大多数FXS患者(&gt；80%)也患有衰弱焦虑和社交功能障碍。人类和FXS的临床前研究已经发现杏仁核异常，杏仁核是处理恐惧、焦虑和社交突出的关键大脑结构。此外，最近对脆性x智力低下基因敲除小鼠(FMR1-KO)的研究发现，广泛存在的抑制性神经传递缺陷导致兴奋性和可塑性异常，特别是在杏仁核。重要的是，杏仁核回路功能障碍可以通过含有GABAA受体的亚基加强强直(突触外)抑制来逆转。重要的是，不与这种受体结合的苯二氮卓类药物对FXS患者的效用有限，因为它们的效果不如FXS患者 这对普通人群是不利的，并受到镇静剂、耐受性和副作用责任的阻碍。相比之下，我们的先导神经活性类固醇化合物可以增强所有GABAA受体，包括那些包含？亚单位的受体，从而为纠正杏仁核回路功能障碍提供机会，并取得更大的疗效。然而，这些有希望的GABAA受体阳性变构调节剂仍然需要改进它们的药代动力学特征。安全性、耐受性、受体选择性和体内疗效的测试也处于早期阶段。因此， 这项提议的目标是与美国国家卫生研究院合作，优化我们的铅系列，以开发一种合成的 GABAA受体的神经活性类固醇正变构调节剂具有必要的效力、疗效、选择性、安全性和类药物(DMPK)特性，至少支持BID口服剂量治疗FXS，特别关注改善焦虑和社交缺陷。化合物筛选将包括确认靶标结合的放射性配基分析，突触和突触外GABAA受体介导的神经传递的电生理学研究，体内和体外药代动力学分析，以及药效学实验。疾病验证研究将包括对GABA对初级神经元反应的复合效应的电生理学、体外可塑性研究，以及FMR1-KO小鼠体内蛋白质合成和行为评估。一种有效治疗FXS患者焦虑和社交缺陷的新疗法将大大改善他们的生活。神经治疗的蓝图可以通过与SAGE治疗公司的合作来促进这一目标的实现。

DESCRIPTION (provided by applicant): Although the predominant feature of Fragile X syndrome is cognitive dysfunction, the vast majority of FXS patients (>80%) also suffer from debilitating anxiety and social dysfunction Human and preclinical studies of FXS have identified abnormalities in the amygdala, a critical brain structure for fear, anxiety and social salience processing. Furthermore, recent studies on fragile x mental retardation gene knockout mice (FMR1-KO) have identified widespread deficits in inhibitory neurotransmission that lead to abnormalities in excitability and plasticity, particularly in the amygdala. Importantly amygdala circuit dysfunction can be reversed by augmenting tonic (extra synaptic) inhibition through ¿-subunit containing GABAA receptors. Importantly, benzodiazepines, which do not bind to this type of receptor, have limited utility in patients with FXS because they are less effective than in the general population and are hampered by sedative, tolerance and side effect liabilities. In contrast, our lead neuroactive steroid compounds can potentiate all GABAA receptors, including those containing the ¿-subunit, thus providing an opportunity to correct amygdala circuit dysfunction and achieve greater efficacy. However, these promising GABAA receptor positive allosteric modulators still require improvements in their pharmacokinetic profile. Testing for safety, tolerability, receptor selectivity and in vivo efficacy are also in early stages. Thus, the goal of this proposal is to partner with the NIH to optimize our lead series to develop a synthetic neuroactive steroid positive allosteric modulator of GABAA receptors with the requisite potency, efficacy, selectivity, safety, and drug-like (DMPK) properties to support at least BID oral dosing for the treatment of FXS, with a particular focus on ameliorating anxiety and social deficits. Compound screening will include, a radioligand assay to confirm target engagement, electrophysiology studies of synaptic and extra-synaptic GABAA receptor mediated neurotransmission, in vivo and in vitro pharmacokinetic analysis, and pharmacodynamic experiments. Disease validation studies will include electrophysiology of compound effects on primary neuron responses to GABA, ex vivo plasticity studies, and in vivo protein synthesis and behavioral assessments in FMR1-KO mice. A new therapeutic that effectively treats anxiety and social deficits in patients with FXS would substantially improve their lives. The Blueprint for Neurotherapeutics can facilitate the realization of this goal through partnership with SAGE Therapeutics.