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Scripps researchers aim for a triple
JUPITER, Fla.—DNA, and the intricate ways its coding affects biology and diseases, has long since been a target of interest for scientists. Until recently, though, RNA has not provided the same kind of success, despite also being an inextricable part of genomics. A recent discovery by scientists from the Florida campus of the Scripps Research Institute, however, has identified a compound that is capable of repairing a specific kind of RNA defect, which could lead to therapeutics for diseases such as Huntington's disease, Spinocerebellar ataxia and Kennedy disease.
The study, "Chemical Correction of Pre-mRNA Splicing Defects Associated with Sequestration of Muscleblind-Like 1 Protein by Expanded r(CAG)-containing Transcripts," was published January 17 in an advance online edition of ACS Chemical Biology. The researchers, led by associate professor Matthew Disney of Scripps Florida, discovered a compound that could target defective RNA, specifically RNA with a triple repeat, a series of three nucleotides repeated several more times than what is normal in the genetic code of affected individuals.
According to Disney, these RNA defects can come about a few ways. A person's genetic code gives them these repeats, he says, and so one can inherit triple repeats. Additionally, "as you get older, those repeats can expand during replication."
"For a long time it was thought that only the protein translated from this type of RNA was toxic," Disney said in a press release. "But it has been shown recently that both the protein and the RNA are toxic. Our discovery of a small molecule that binds to RNA and shuts off its toxicity not only further demonstrates that the RNA is toxic, but also opens up new avenues for therapeutic development, because we have clearly demonstrated that small molecules can reverse this type of defect."
Disney notes that they have "been trying to get small molecules that are bioactive against targeting RNA for probably the past five years," but that unlike DNA, there is much less information regarding natural products that specifically target RNA. While RNA is already used in therapeutics, those consist of small molecules that target the ribosome, Disney explains, not a specific messenger RNA as the Scripps researchers' new compounds do.
"Part of the reason that we think there's difficulty in [targeting RNA] is because if you look at the RNA content in the cell, the ribosome's 80 to 90 percent of the total content," says Disney. "And so being able to target specifically one messenger RNA in a sea of ribosome is extremely difficult. The compound has to be fairly selective in order to do that. It's a selectivity issue in terms of relative expression levels of all the RNAs in a cell. And it's a lack of knowledge base on small molecules that can specifically target an RNA."
Using a query molecule known as 4', 6-diamidino-2-phenylindole (DAPI) as a chemical and structural template, Scripps Research scientists searched for similar compounds that could more actively inhibit a toxic CAG triplet repeat, which is found in Huntington's disease. They were able to find a compound that could effectively inhibit the RNS toxicity of the triplet repeat in patient-derived cells, exhibiting an improvement in early-stage abnormalities.
"The toxic RNA defect actually sucks up other proteins that play critical roles in RNA processing, and that is what contributes to these various diseases," Disney noted in a press release. "Our new compound targets the toxic RNA and inhibits protein binding, shutting off the toxicity. Since the development of drugs that target RNA is extremely challenging, these studies can open up new avenues to exploit RNA drug targets that cause a host of other RNA-mediated diseases."
Disney says that the team has been able to "design and optimize a compound for biological activity that targets the CAG repeats in Huntington 's disease and then reverses one of the defects that's been most recently associated with the disease in patient-derived cells." They have also designed a compound that targets the triplet repeat present in myotonic dystrophy, an incurable form of muscular dystrophy, with the compounds proving to be bioactive in both cell models and animal models when it comes to reversing defects. Repeating RNA defects appear in a variety of other diseases in addition to Huntington's and myotonic dystrophy, such as Fragile X syndrome. In addition, it has recently been discovered that there is a correlation between people with Lou Gehrig's disease, also known as ALS, and a GGGCC repeat, Disney adds.
"The number of diseases that are caused by these repeating RNAs, I think, is expanding considerably, if not exponentially," he says.
The work is far from over, Disney notes, as the team already has plans for how to further its discoveries.
"What we need to do next—I think this is where the real impact in making a therapy against Huntington 's disease is—is we want to take this compound and try to use it as a lead to stop translation of toxic proteins," he says. "Huntington's repeat is a CAG repeat, but it's in a messenger RNA that gets made into protein. And so the next thing we want to do is not only shut off the toxicity of the RNA but stop that RNA's ability to be translated into a protein. And so there's a lot of work that remains to be done in that area."
The lead author of this study is Amit Kumar of Scripps Research, with other authors including Raman Parkesh and Jessica Childs-Disney, both of Scripps Research, and Lukasz J. Sznajder and Krzysztof Sobczak of Adam Mickiewicz University in Poland. Support for the study came from the National Institutes of Health, the Polish Ministry of Science and Higher Education, Camille & Henry Dreyfus Foundation and the Research Corporation for Science Advancement.
Camille & Henry Dreyfus Foundation
Research Corporation for Science Advancement