Inhibition of an RNA-binding protein as a treatment for fragile X syndrome

  • Awarded: 2020
  • Award Type: Pilot
  • Award #: 668241

Fragile X syndrome (FXS), an autism spectrum disorder (ASD) and the most common genetic form of intellectual disability in males, is caused by the loss of function of FMR1. The protein encoded by this gene, FMRP, is an RNA-binding protein (RBP) that acts as a translational repressor, binding to neuronal transcripts and decreasing their translation by the ribosome. In the absence of functional FMRP, neuronal protein synthesis is constitutively elevated, leading to the impairment of several pathways that rely on activity-dependent stimulation of synaptic translation. This blunting of synaptic plasticity is thought to be central to the etiology of FXS.

Therapeutic strategies aimed at restoring individual pathways downstream of FMRP, such as the metabotropic glutamatergic or GABAergic systems, have had limited clinical success. An entirely novel therapeutic approach is to target proteins that bind FMRP-bound transcripts and act synergistically or antagonistically to FMRP-mediated translational repression.

Gene Yeo and his colleagues study the role of RBPs in post-transcriptional gene regulation. His team has identified RBPs that co-occupy mRNA targets of FMRP and enhance translation of these transcripts. Thus, the team believes a specific RBP acts antagonistically to FMRP, making it a potential drug target for the treatment of FXS.

Yeo‘s team is using CRISPR genome editing to generate human induced pluripotent stem cell (iPSC)-based models of FXS to test if depletion of this candidate RBP can normalize exaggerated translation of FMRP mRNA targets and restore disease-relevant molecular, cellular and functional deficits. To this end, they are using ribosome profiling, synaptic connectivity assays and electrophysiological readouts in iPSC-derived cortical organoids. The group is also investigating if genetic and antisense oligonucleotide-mediated depletion of the RBP in Fmr1 knockout mice can normalize behavioral phenotypes.

With this work, Yeo’s team aims to validate this promising new therapeutic avenue for FXS1. If successful, his team plans to identify small molecule inhibitors of the RBP. Yeo hopes that similar approaches will also prove feasible for other ASD subtypes associated with dysregulation of protein translation.


1.NussbacherK. et al. Neuron 102, 294-320 (2019) PubMed
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