Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy
Estefanía Cerro-Herreros, Irene González-Martínez, Nerea Moreno, Jorge Espinosa-Espinosa, Juan M. Fernández‐Costa, Anna Colom-Rodrigo, Sarah J. Overby, David Seoane-Miraz, Javier Poyatos‐García, Juan J. Vílchez, Adolfo López de Munaín, Miguel A. Varela, Matthew J. A. Wood, Manuel Pérez‐Alonso, Beatriz Llamusí, Rubén Artero
Abstract
, antagomiR-218 reached 40-60 pM 2 weeks after injection, rescued molecular and functional phenotypes in a dose- and time-dependent manner, and showed a good toxicity profile after a single subcutaneous administration. In muscle tissue, antagomiR rescued the normal subcellular distribution of Mbnl1 and did not alter the proportion of myonuclei containing CUG foci. In patient-derived cells, antagomiR-218 improved defective fusion and differentiation and rescued up to 34% of the gene expression alterations found in the transcriptome of patient cells. Importantly, miR-218 was found to be upregulated in DM1 muscle biopsies, pinpointing this microRNA (miRNA) as a relevant therapeutic target.