RNA-based approach shows promise for DM1 in cell models
AntimiRs could become 'viable' strategy for treating myotonic dystrophy type 1
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Treatment with antimiRs, an RNA-based therapy approach, was able to correct molecular defects in a cell model of myotonic dystrophy type 1 (DM1) — a form of muscular dystrophy — according to the results of a new study.
The researchers called their work “a significant step forward,” and noted that this strategy potentially “could be beneficial for treating multiple clinical forms” of DM1, the most common type of muscular dystrophy in which symptoms start in adulthood.
EstefanÃa Cerro, PhD, the study’s first author, said further testing will be needed in people living with the genetic disease.
“If clinical trials prove successful, antimiRs could become a viable therapeutic strategy for DM1, offering hope to patients affected by this debilitating disease,” Cerro said in a press release.
The study, “AntimiR treatment corrects myotonic dystrophy primary cell defects across several CTG repeat expansions with a dual mechanism of action,” was published in the journal Science Advances.
Investigating RNA types to find new treatments for DM1
RNA, short for ribonucleic acid, is a key type of molecule in living cells. There are many different forms of RNA, each with a specific purpose.
Likely the best-known type of RNA is messenger RNA, an intermediary molecule that’s produced when genes are used in the protein-making process. The genetic code is copied over from a cell’s DNA into messenger RNA, which is then used as a template to produce protein by the cell’s ribosomes, essentially its protein-making machines.
A problem affecting messenger RNA is the underlying cause of DM1. In this type of muscular dystrophy, mutations in a gene called DMPK lead to the production of an abnormally long messenger RNA. This unusually long molecule forms clumps inside cells, and interferes with the production of proteins.
In particular, these messenger RNA clumps stick to a protein called MBNL1, which normally helps to regulate how RNA is processed. In DM1, MBNL1 gets stuck so it cannot perform its normal function, and as a result, hundreds of genes become dysregulated, ultimately leading to muscle cell damage that drives disease symptoms.
In this study, a team of scientists from Spain set out to increase MBNL1 functionality in DM1 cells by targeting a different type of RNA: microRNA. These are small pieces of RNA that don’t code for protein, but instead act to regulate the activity of protein-coding genes. The scientists who discovered microRNA were recently awarded the Nobel Prize in Physiology or Medicine.
Here, the scientists specifically focused on two microRNAs, dubbed miR-23b and miR-218, which normally act to reduce levels of the MBNL1 protein. In DM1, cellular stress leads to unusually high levels of these microRNAs, which exacerbates reduced MBNL1 protein activity in a vicious cycle. The team reasoned that, if they could reduce levels of these microRNAs, they could interrupt the cycle to restore MBNL1 protein activity, ultimately improving muscle cell health.
Our study in DM1 human-derived mature [muscle cells] revealed that the most critical disease-associated molecular alterations could be reversed by blocking miR-23b and miR-218, two [microRNAs] that are natural repressors of MBNL1.
For their experiments, the team used lab-made pieces of RNA called antimiRs, which can be designed to target and neutralize specific microRNAs. The effects of antimiRs targeting miR-23b and miR-218 were tested in a panel of eight muscle cell lines derived from people with DM1.
The results showed that this antimiR approach could successfully reduce the microRNA levels as designed. That, in turn, consistently led to an increase in MBNL1 protein levels and normalized the activity of genes regulated by MBNL1. The antimiR treatment also resulted in fewer abnormal clumps of DMPK messenger RNA, and treated cells were better able to grow into mature muscle cells.
“Our study in DM1 human-derived mature [muscle cells] revealed that the most critical disease-associated molecular alterations could be reversed by blocking miR-23b and miR-218, two [microRNAs] that are natural repressors of MBNL1,” the researchers wrote.
Researchers already advancing antimiR ID’d in study
Rubén Artero, PhD, senior author of the study, noted that these findings have “demonstrated the great potential of antimiRs to treat different forms of myotonic dystrophy type 1 by releasing the MBNL1 protein and enhancing its production.”
A particular antimiR dubbed antimiR-23b-V2 showed the most potent effects, so the researchers have selected this molecule for development as a potential DM1 treatment. The team noted that it showed promising effects in cells with varying lengths of DMPK mutations, implying that this approach may be useful in a wide range of DM1 patients.
“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,” said Gisela Nogales, PhD, co-author of the study.
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