A new study reveals a promising therapy using a molecule that blocks microRNAs to treat myotonic dystrophy type 1

Monday, 14 October 2024 - Research

Scientist loading samples to a RT-PCR thermal cycler at the laboratory. Image credit: anamejia18 - Getty Images.

This breakthrough highlights the importance of continuing research into RNA-targeted therapies to treat genetic disorders like this disease, which until now has lacked effective treatment options
The research findings were recently published in Science Advances, the open-access multidisciplinary journal of the American Association for the Advancement of Science

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 prestigious open-access multidisciplinary journal of the American Association for the Advancement of Science (AAAS).

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.

About Myotonic Dystrophy Type 1

DM1 is a rare genetic disease that currently has no effective treatment, affecting approximately 1 in 8,000 people in the population. The disease characteristically affects multiple systems and organs, is progressive, and can appear at any time in life. It also manifests earlier and more severely when passed on to offspring.

DM1 primarily affects the muscles of the limbs, causing weakness and atrophy, compromising mobility, as well as affecting cognitive functions and causing cardiac arrhythmias, among many other symptoms.

Reference

Cerro-Herreros E, Núñez-Manchón J, Naldaiz-Gastesi N, Carrascosa-Sàez M, García-Rey A, Losilla DP, González-Martínez I, Espinosa-Espinosa J, Moreno K, Poyatos-García J, Vilchez JJ, de Munain AL, Suelves M, Nogales-Gadea G, Llamusí B, Artero R. AntimiR treatment corrects myotonic dystrophy primary cell defects across several CTG repeat expansions with a dual mechanism of action. Sci Adv. 2024 Oct 11;10(41):eadn6525. DOI: 10.1126/sciadv.adn6525.

Funding

This work was financially supported by the following: "la Caixa" Banking Foundation grant HR17-00268 (R.A.), Generalitat Valenciana grant PROMETEO/2020/081 (R.A), Instituto de Salud Carlos III grant PI22/00104 (G.N.-G.), AFM-Telethon grant #24757 (G.N.-G.), Ministerio de Ciencia e Innovación grant CNS2022-135519 (G.N.-G.), Ministerio de Ciencia e Innovación grant PID2020-118730RB-I00 (M.S.), Generalitat Valenciana post-doctoral fellowship APOSTD/2019/142 (E.C.-H.), Generalitat Valenciana predoctoral fellowship FDEGENT/2020/001 (I.G.-M.), Instituto de Salud Carlos III I-PFIS fellowship grant IFI20/00022 (J.N.-M.), Headstart of Eit Health (EU), project "ARTHEx-DM1" (2020-HS-0215) (B.L.), CDTI NEOTEC grant SNEO-20201136 (B.L.), GVA-IVACE grant IMIDTA/2021/65) (B.L.), and Torres Quevedo post-doctoral fellowship PTQ2020-011110 (E.C.-H.). Additional funding was from the project "DISMIOTATX" with reference CPP2022-009960, funded by MCIN/AEI/10.13039/501100011033 and, as appropriate, by the "European Union NextGenerationEU/PRTR" to (B.L, G.N.-G., and R.A).

News story shared with INCLIVA.