Ahulkenoids restore multiple phenotypes in vitro and in vivo in Myotonic Dystrophy type 1

Myotonic dystrophy type 1 is an autosomal dominant disorder without available treatment to slow or stop disease progression nowadays. It is clinically characterized by a progressive muscular weakness and multisystem degeneration. In this study, we characterized the impact of a new family of FKBP12 “reshapers” (known as ahulkenoids). Treatment with different ahulkenoids reversed the accumulation of oxidative stress, the impaired cell viability and proliferation as well as mitochondrial activity and metabolism defects in DM1 derived primary fibroblasts. Moreover, RNAseq analysis confirmed the restoration of molecular pathways related to cell cycle and cell metabolism. Importantly, treatment with ahulkenoids significantly maintained locomotor activity and extended lifespan of a Drosophila model of the DM1 disease. In summary, our results revealed the benefits of a new family of compounds, entitled ahulkenoids, in the pre-clinical setting of DM1 Overall design: DM1-derived fibroblasts treated with 0.1 µM AHK7 for 72 h.