Identifying Therapeutics for Treating Rett Syndrome Using Nuclear Size as a Proxy for Long Gene Mis-regulation

Michael Greenberg | Harvard University

$110,000 AWARDED

Recent studies from the Greenberg lab identified the mis-regulation of long-gene expression caused by MeCP2 defect. At the cellular level, the resulting phenotype manifests in the dysfunction or loss of neuronal synapses that underlie learning and memory. Greenberg and colleagues hypothesize that restoring the expression of mis-regulated long genes and synaptic development may be key to treating Rett. They propose to screen for novel small molecules that can reverse Rett-associated gene expression defects using a high-throughput imaging assay in which decreased nuclear size will be used as a proxy for long-gene up-regulation. This screen will include a cohort of synaptic growth-enhancing (SGE) compounds that they identified in a previous collaboration with Roche as well as an unbiased analysis of a large-scale small molecule library. Identified hits will be further evaluated in a variety of cell-based assays including iPS cell derived neurons, and promising therapeutic candidates will then be analyzed in vivo for their ability to reverse Rett-associated phenotypes. The proposed experiments will thus target both the pathological cause and the phenotypic outcome of Rett, and have the potential to provide exciting therapeutic options for treating this devastating disorder.

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