Two birds with one stone
In diseases associated with an increase in the number of RNA repeats, mutant genes contain dozens or even hundreds of repeating short chains of DNA "letters". In cells where these mutant genes are active, DNA is copied into RNA molecules, and the resulting abnormal RNAs can harm in various ways, for example, organize into structures that are toxic to cells.
A new treatment strategy for a group of diseases known as nucleotide repeat expansion, which affects millions of people, has yielded a positive result in trials conducted by researchers from the Scripps Research Institute, USA. The study gives hope for the cure of more than 40 diseases, including Huntington's disease and variants of amyotrophic lateral sclerosis (ALS), which arise as a result of the expansion of nucleotide repeats.
Researchers have shown that a molecule of a potential drug developed by them can neutralize toxic RNA, which causes two different disorders: type 1 myotonic dystrophy (MD1) and Fuchs corneal endothelial dystrophy (EDF). In the latter case, this happens with the help of an unexpected but powerful mechanism.
Genetic diseases that have no treatment
According to various estimates, MD1 affects about 140,000 people in the United States. It can manifest itself both in infancy and in adulthood. And although MD1 does not always affect life expectancy, it is accompanied by a complex of severe manifestations, including muscle weakness, pain, cataracts, respiratory and gastrointestinal problems. The disease is caused by a mutant copy of the DMPK gene, whose RNAs contain tens to hundreds of repeats in the CUG trinucleotide RNA.
EDF is associated with a progressive violation of the transparency of the cornea of the eye, and often requires corneal transplantation. It is relatively common: studies show that EDF manifests itself in at least a few percent of people of the Caucasian race over the age of 50. The disease is caused by a mutant version of the TCF4 gene, whose RNAs also contain abnormally long repeats of the CUG trinucleotide.
These two diseases are associated with mutations in different genes, and, consequently, manifest themselves in different types of cells, but develop almost by the same toxic mechanism: an abnormally long sequence of CUG repeats causes RNA copied from the gene to form structures that "stick" to some other proteins, preventing them from realizing their a function in a cell. Depletion of one of these deactivated proteins, MBNL1, is a particularly important cause of cell damage and the development of symptoms in MD1 and EDF.
Encouraging results of preclinical trials
For the new study, the team used advanced computational methods and created a small organic molecule that selectively binds to abnormal CUG expansions in RNA in cells affected by MD1 and EDF, preventing the capture of the MBNL1 protein.
The researchers showed on cell lines obtained from MD1 patients, as well as on animal models, that the therapeutic molecule they developed successfully reduced the depletion of MBNL1 and prevented the loss of its function.
In EDF cells, the experimental drug also prevented signs of the disease, but this time through a different and potentially more powerful mechanism. In EDF, the mutation of the disease–causing gene occurs in the non-coding part of the gene - in the intron. Usually, when copying introns, they are almost immediately cut out of RNA and destroyed by cell recycling systems. In EDF, the presence of CUG expansion interferes with excision of the pathological intron. However, the researchers found that the therapeutic molecule makes it possible to remove the intron, that is, the abnormal RNA element is not just blocked, but also destroyed.
Thus, the results of the study indicate a promising possibility not only of blocking RNA repeats, but also of their destruction, which will give a more persistent therapeutic effect.
Researchers are also working with a similar approach to develop potential drugs to treat diseases associated with the expansion of other trinucleotides, including CAG repeats that mediate the progressive and fatal neurological disorder Huntington's disease.
Article by A.J.Angelbello et al. A Small Molecule that Binds an RNA Repeat Expansion Stimulates Its Decay via the Exosome Complex is published in the journal Cell Chemical Biology
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on Scripps Research: Two-birds-one-stone strategy shows promise in RNA-repeat expansion diseases.