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（约80%）也患有使人衰弱的焦虑和社交功能障碍，FXS的人类和临床前研究已经发现杏仁核异常，杏仁核是恐惧、焦虑和社交显著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（FMR1-KO）的研究发现，抑制性神经传递普遍存在缺陷，导致兴奋性和可塑性异常，尤其是杏仁核。重要的是，杏仁核回路功能障碍可以通过含有GABAA受体的¿-亚基增强强直性（突触外）抑制来逆转。重要的是，苯二氮卓类药物不与这种类型的受体结合，在FXS患者中的效用有限，因为它们的效果不如

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.