Neuroactive Steroid GABAA Receptor Positive Modulators for Fragile X Syndrome

描述（由申请人提供）：尽管脆性X综合征的主要特征是认知功能障碍，但绝大多数FXS患者（>80%）也患有使人衰弱的焦虑和社会功能障碍。FXS的人类和临床前研究已经确定了杏仁核的异常，杏仁核是恐惧、焦虑和社会显着性处理的关键大脑结构。此外，最近对脆性X智力低下基因敲除小鼠（FMR 1-KO）的研究已经确定了抑制性神经传递的广泛缺陷，导致兴奋性和可塑性异常，特别是在杏仁核中。重要的是，杏仁核回路功能障碍可以通过增强通过含有GABAA受体的<$-亚基的紧张性（突触外）抑制来逆转。重要的是，不与这种类型的受体结合的苯二氮卓类药物在FXS患者中的效用有限，因为它们的有效性低于FXS患者。 一般人群，并受到镇静剂，耐受性和副作用责任的阻碍。相比之下，我们的主要神经活性类固醇化合物可以增强所有GABAA受体，包括那些含有<$-亚基的受体，从而提供了纠正杏仁核回路功能障碍并实现更大疗效的机会。然而，这些有前途的GABAa受体阳性变构调节剂仍需要改善其药代动力学特征。安全性、耐受性、受体选择性和体内功效的测试也处于早期阶段。因此 该提案的目标是与NIH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，其具有必要的效力、功效、选择性、安全性和药物样（DMPK）性质，以支持至少BID口服给药用于治疗FXS，特别关注于改善焦虑和社交缺陷。化合物筛选将包括确认靶点接合的放射性配体测定、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化合物对初级神经元对GABA反应的电生理学影响、离体可塑性研究以及FMR 1-KO小鼠的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。神经治疗学蓝图可以通过与SAGE Therapeutics的合作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.