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.

Public Health Relevance

60,000 Americans have Fragile X syndrome (FXS) yet, there are no FDA approved therapies. Aside from intellectual disability, the vast majority of FXS patients (>80%) suffer from debilitating anxiety and social dysfunction. The drug development program delineated in this application will leverage a compelling new discovery of GABA deficits in the key fear/anxiety center of the brain, and deliver a first in class medication for the treatment of FXS and possibly other patients suffering from Autism Spectrum Disorder.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZNS1-SRB-R (61))
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Cywin, Charles L
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Sage Therapeutics, Inc.
United States
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