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Cohesin is a multi-subunit protein complex that forms a ring-like structure around DNA. Cohesin is essential for sister chromatid cohesion, chromosome organization into looped domains, DNA damage repair and transcription regulation. Germline loss-of-function mutations in cohesin subunits cause a family of developmental disorders termed cohesinopathies. In addition, cohesin is one of the most frequently mutated protein complexes in cancer, including myeloid blood cancers, with recurrent somatic loss-of-function mutations in core components of the cohesin ring and its modulators. Importantly, cancer-associated mutations in cohesin rarely affect chromosome integrity, but instead selectively impair chromatin organization and gene-regulatory functions. However, how cohesin affects gene activity remains enigmatic, offering no clues towards intervention. Consequently, there are no targeted therapeutic approaches available to treat disease involving cohesin mutations. Recently, we discovered that cohesin mutations common in myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) disrupt both transcription and RNA splicing. Through detailed investigation of gene activity and splicing profiles in cohesin-mutant AML cells, we hope to discover novel opportunities for therapeutic targeting. Our goal is to leverage this knowledge to develop targeted approaches that will selectively kill cohesin-mediated disease. The findings from these studies have the potential to lead directly to one or more clinical trials within the next several years. 

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of somatosensory dysfunction to the expression of ASD-like traits (Orefice et al., Cell, 2016; Orefice et al., unpublished; Tasnim et al., unpublished).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.

The focus of this proposal is the development of capsules, a technological platform with applications to isolation, growth, sorting, dialysis and genomic analysis of single cells or molecules. The platform addresses multiple needs ranging from measurement and diagnostics, screening, and potentially cell-based therapy. We recently developed a method to produce capsules robustly, with a novel composition that satisfies design requirements for these applications. A report-of-invention has been filed with HMS OTD (filing number HU8902). In this pilot grant, we have two specific aims: first, to extend the diversity of capsule compositions, and to characterize their biophysical properties and their biocompatibility. Second, to develop applications in single cell genomics. These efforts will characterize capsules as a novel and versatile reagent.