Integrated evaluation of the antimiR’s therapeutic potential. Credit: Science Advances (2024). DOI: 10.1126/sciadv.adn6525

A team of researchers has identified a promising therapy based on antimiRs to treat myotonic dystrophy type 1 (DM1), a complex genetic disorder caused by an abnormally high number of CTG repeats (a specific type of RNA sequence) in the DMPK gene. The results of their research have just been published in Science Advances.

The work has been carried out by researchers from the Human Translational Genomics Group of Instituto de Investigación Sanitaria de INCLIVA-Universitat de València (UV), led by Dr. Rubén Artero, in collaboration with the company Arthex Biotech, which emerged from research findings from INCLIVA and UV, the Badalona Neuromuscular Research Group (GRENBA) at Germans Trias i Pujol Research Institute (IGTP), the Biogipuzkoa Health Research Institute and the Health Research Institute Hospital La Fe.

The study, conducted on eight muscle cell lines directly derived from biopsies of patients with DM1, demonstrated that blocking small regulatory RNAs, known as microRNAs, through perfectly complementary molecules, called antimiR, increases the expression of the essential protein MBNL1, which is usually repressed in DM1, causing muscle dysfunction.

DM1 arises due to a reduction in MBNL1 protein, contributing to a wide range of clinical symptoms associated with the disease. The study showed that untreated cells from patients with DM1 exhibited elevated levels of miR-23b and miR-218, microRNAs that repress MBNL1.

In an encouraging development, treatments with antimiRs not only increased MBNL1 levels but also significantly improved the functions normally carried out by this protein and muscle cells. Surprisingly, the therapy also reduced the number of molecules with expansions responsible for the disease, preventing the formation of accumulations of expanded molecules and MBNL1 protein, known as “ribonuclear foci.”

The best-performing antimiR was able to reverse 68% of the deregulated genes, offering hope for broader therapeutic benefits in DM1 patients, regardless of the intrinsic genetic variations among the cell lines used.

Dr. Gisela Nogales, leader of the GRENBA group at IGTP and author of the study, explains, “Thanks to the collaboration of patients in this work, several cell models derived from them have been studied, showing that antimiRs could have therapeutic potential in patients with different degrees of DM1 severity.”

Dr. Rubén Artero, corresponding author of the study, adds that “this study has demonstrated the great potential of antimiRs to treat different forms of myotonic dystrophy type 1 by releasing the MBNL1 protein and enhancing its production.”

Dr. Estefanía Cerro, first author of the paper, notes, “If clinical trials prove successful, antimiRs could become a viable therapeutic strategy for DM1, offering hope to patients affected by this debilitating disease.”

This advance underscores the importance of continuing research into RNA-targeted therapies to address genetic disorders like DM1, which to date have not had effective treatment options.