Medicine in Drug Discovery · Published 2025-12-16 · DOI 10.1016/j.medidd.2025.100244
Fragile X syndrome (FXS), a leading inherited cause of intellectual disability and autism, arises from loss of the RNA-binding protein FMRP and consequent dysregulation of synaptic mRNA translation. No clinically approved therapies exist to restore FMRP function. A recent study showed that a Tat-conjugated FMRP fragment spanning residues 1–297 (FMRP N-tat) can transiently reduce hyperexcitability in an FXS mouse model, supporting peptide replacement as a feasible therapeutic strategy. Extending this concept, Leguay et al. demonstrated in FXS patient iPSC-derived neurons that N-tat reconstitutes interactions with endogenous protein partners correcting dysregulated translation and mitochondrial defects. However, despite recapitulating several functions of full-length FMRP, the in vivo effects of N-tat remain short-lived, highlighting challenges in stability and the potential need for additional functional domains. Herein, this commentary outlines both the promise of N-tat–based protein replacement and the remaining gaps that must be addressed to achieve clinically durable restoration of FMRP function.
Abstract from DOAJ. Public domain (CC0 1.0).
Read the article at the publisher →