Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by impairments in social communication and interactions, and restricted and repetitive behaviors. ASD is well-established to be associated with aberrant reactivity in multiple sensory domains, including touch, and indeed aberrant sensory reactivity is now considered a key diagnostic feature of ASD. We have used a range of mouse genetic models of ASD combined with behavioral testing, synaptic analyses, and electrophysiology to define both the etiology of aberrant tactile sensitivity in ASD and the contribution of somatosensory dysfunction to the expression of ASD-like traits (Orefice et al., Cell, 2016; Orefice et al., unpublished; Tasnim et al., unpublished). We found that mutations in genes associated with both syndromic and non-syndromic forms of ASD cause tactile dysfunction, and that the RTT- and autism-associated genes Mecp2, Shank3, and Gabrb3 function cell autonomously in peripheral somatosensory neurons for normal tactile behaviors. Remarkably, these somatosensory deficits during development contribute to aberrant social behaviors, including anxiety-like behaviors and social interactions, in adulthood. Our findings raise the exciting possibility that GABAA receptor agonists, which attenuate the activity of peripheral mechanosensory neurons, may be useful for treating tactile hypersensitivity and thus anxiety and social impairments in ASD patients. A key consideration for our work is that physicians are reluctant to prescribe GABAA receptor agonists and positive allosteric modulators because of undesirable side effects, including sedation, and serious complications associated with interference of brain development. Therefore, we aim to use peripherally-restricted GABAA receptor agonists and modulators, compounds that do not cross the blood-brain barrier, to treat tactile dysfunction and core ASD behaviors. Importantly, peripherally-restricted GABAA receptor drugs should not promote undesirable side effects observed with all currently used, FDA-approved GABAA receptor agonists that act in the brain. Thus, for this Q-FASTR application, we proposed to determine the efficacy of isoguvacine, a known peripherally-restricted GABAA receptor agonist, as well as novel isoguvacine and nonbenzodiazepine derivatives designed to be peripherally-restricted, for treating tactile hypersensitivity and core ASD behaviors in animal models of ASD. Indeed, we were able to show that isoguvacine reduces tactile sensitivity in mice. Also, chronic isoguvacine treatment improves a subset of ASD-related phenotypes in mice such as overall body condition, body weight, and anxiety-like behaviors. This project, which was co-funded by BBA, has moved into Lab1636, a major strategic R&D alliance between Harvard and the healthcare investment firm Deerfield, where these results will be validated and advanced to late-stage preclinical development.
Funding
Funding Duration
July 1, 2018 - June 30, 2020