Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease s...

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Detalles Bibliográficos
Autores: Cerro Herreros, Estefanía, González Martínez, Irene, Moreno, Nerea, Espinosa Espinosa, Jorge, Fernández Costa, Juan M., Colom Rodrigo, Anna, Overby, Sarah J., Seoane Miraz, David, Poyatos García, Javier, Vilchez, Juan J., López de Munain Arregui, Adolfo José, Varela, Miguel A., Wood, Matthew J., Pérez Alonso, Manuel, Llamusí, Beatriz, Artero, Rubén
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/53616
Acceso en línea:http://hdl.handle.net/10810/53616
Access Level:acceso abierto
Palabra clave:CTG repeat expansions
MBNL1 protein
alternative splicing
antisense oligonucleotide
microRNAs
myotonic dystrophy
therapeutic gene modulation
tissue distribution
transcriptomics
Descripción
Sumario:Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease symptoms such as muscle weakness and atrophy and myotonia, yet upregulation of endogenous MBNL1 levels may compensate for this sequestration. Having previously demonstrated that antisense oligonucleotides against miR-218 boost MBNL1 expression and rescue phenotypes in disease models, here we provide preclinical characterization of an antagomiR-218 molecule using the HSALR mouse model and patient-derived myotubes. In HSALR, antagomiR-218 reached 40-60 pM 2weeks 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.

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