| Summary: | Autism Spectrum Disorder (ASD) is a collection of developmental disabilities characterized by outward features, such as impaired socialization skills and repetitive behaviors, and often associated with broad health complications that together carry lifelong impact. Unfortunately, ASD symptoms occur at the nexus of higher-order cognitive functions, which arise through inordinately complex cellular and molecular processes. This pleiotropic nature means that, in many cases, ASD remains poorly understood at the mechanistic level. Tremendous efforts are underway to define the etiology of ASD, but there must be equally rigorous attention to the systems employed to model these genetics in order to ensure accurate insights into their pathophysiology and treatment options.
We sought to extend the current state of animal models for two of the most prevalent monogenic causes of ASD and investigate their therapeutic potential. Fragile X syndrome is a trinucleotide repeat disorder where repeat expansion in the FMR1 5’ untranslated region triggers its methylation and represses its transcription. Yet we were unable to reproduce this methylation when we aggressively expanded the repeat length of mouse Fmr1, suggesting fundamental differences in species biology that may limit the utility of mice for studying treatment in Fragile X. We also initiated a project to target Rett syndrome - a highly debilitating condition typically caused by de novo loss-of-function mutations in MECP2 - with emerging RNA-based gene therapy approaches. We theorized that the A-to-I converting REPAIR system was capable of recoding all Rett nonsense mutations into tryptophan, and created a proof-of-concept tryptophan model that lacked any discernible Rett phenotypes. We also validated REPAIR editing in vitro as the first step towards a treatment to reverse Rett syndrome in patients. Together, these models contribute valuable insights into the relationship between genes and mechanisms, and provide a path forward for potential therapeutic development.
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