Genome complexity: how humans correct errors (Introduction)

by David Turell , Saturday, November 07, 2020, 20:40 (1477 days ago) @ David Turell

An attempt to develop drugs to counteract genome mistakes:

https://phys.org/news/2020-11-two-birds-one-stone-strategy-rna-repeat-expansion-disease...

"A new strategy for treating a variety of diseases known as RNA-repeat expansion disorders, which affect millions of people, has shown promise in proof-of-principle tests conducted by scientists at Scripps Research.

"The results suggest that someday, a handful of well-targeted drugs might be able to treat the more than 40 human disorders—including Huntington's disease and variants of amyotrophic lateral sclerosis (ALS)—that arise from RNA-repeat expansions.

"'This study lays a foundation for the development of drugs that can address multiple repeat-expansion diseases by targeting shared abnormal structures on their RNAs,"

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"In RNA-repeat expansion diseases, mutant genes contain excess DNA in the form of dozens or even hundreds of repeating short strings of DNA "letters." In cells where these mutant genes are active, that DNA is copied out into RNA molecules on the way to being translated into proteins. The resulting abnormal RNAs can cause trouble in a variety of ways, such as by folding up into structures that are toxic to cells.

"In the study, published in Cell Chemical Biology, the scientists showed that a potential drug molecule they developed can neutralize the toxic RNA that causes two distinct repeat-expansion disorders, myotonic dystrophy 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD). In the latter case, it can do so by an unexpected but powerful mechanism.

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"These disorders arise from different mutant genes, and consequently appear in different cell types, but involve virtually the same toxic mechanism: In each case, the inclusion of an abnormally long sequence of CUG repeats causes the RNA copied from the gene to form structures that are "sticky" to certain other proteins in the cell, and effectively capture them—preventing them from doing their jobs in the cell. The depletion of one of these captured proteins, MBNL1, is a particularly important cause of cell damage and symptoms in DM1 and FECD.

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"Targeting toxic RNAs with small organic molecules that can be put into pill form has generally been very challenging, so far, Disney notes, but the finding in this study points to the promising possibility of using such molecules not just to block bad RNAs but to trigger their destruction.

"If a drug causes a toxic RNA to be destroyed instead of merely blocking it, then the effect should be longer lasting," he says.

"Having performed their proof-of-principle demonstration, he and his team, which includes a startup biotech company, Expansion Therapeutics, are continuing to develop the molecule tested in the study as a potential drug treatment for DM1 and FECD.

"The researchers also are taking a similar approach in developing potential drug treatments for RNA repeat-expansion diseases involving CAG repeats, which include the progressive and fatal neurological disorder known as Huntington's disease."

Comment: This study shows how human ingenuity can solve the errors problem. In our country this error rate is .0000000.424%. Not nice for those affected, but a tiny error rate.