Scripps researchers aim for a triple

New compound capable of repairing RNA defects in diseases such as Huntington’s

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JUPITER, Fla.—DNA, and the intricate ways its coding affectsbiology and diseases, has long since been a target of interest for scientists.Until recently, though, RNA has not provided the same kind of success, despitealso being an inextricable part of genomics. A recent discovery by scientistsfrom the Florida campus of the Scripps Research Institute, however, has identifieda compound that is capable of repairing a specific kind of RNA defect, whichcould lead to therapeutics for diseases such as Huntington's disease,Spinocerebellar ataxia and Kennedy disease.
The study, "Chemical Correction of Pre-mRNA Splicing DefectsAssociated with Sequestration of Muscleblind-Like 1 Protein by Expandedr(CAG)-containing Transcripts," was published January 17 in an advance onlineedition of ACS Chemical Biology. Theresearchers, led by associate professor Matthew Disney of Scripps Florida,discovered a compound that could target defective RNA, specifically RNA with atriple repeat, a series of three nucleotides repeated several more times thanwhat is normal in the genetic code of affected individuals.
According to Disney, these RNA defects can come about a fewways. A person's genetic code gives them these repeats, he says, and so one caninherit triple repeats. Additionally, "as you get older, those repeats canexpand during replication."
"For a long time it was thought that only the proteintranslated 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 toxicitynot only further demonstrates that the RNA is toxic, but also opens up newavenues for therapeutic development, because we have clearly demonstrated thatsmall molecules can reverse this type of defect."
Disney notes that they have "been trying to get small moleculesthat are bioactive against targeting RNA for probably the past five years," butthat unlike DNA, there is much less information regarding natural products thatspecifically target RNA. While RNA is already used in therapeutics, thoseconsist of small molecules that target the ribosome, Disney explains, not aspecific 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, theribosome's 80 to 90 percent of the total content," says Disney. "And so beingable to target specifically one messenger RNA in a sea of ribosome is extremelydifficult. The compound has to be fairly selective in order to do that. It's aselectivity issue in terms of relative expression levels of all the RNAs in acell. And it's a lack of knowledge base on small molecules that canspecifically 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 moreactively inhibit a toxic CAG triplet repeat, which is found in Huntington'sdisease. They were able to find a compound that could effectively inhibit theRNS toxicity of the triplet repeat in patient-derived cells, exhibiting animprovement in early-stage abnormalities.
"The toxic RNA defect actually sucks up other proteins thatplay critical roles in RNA processing, and that is what contributes to thesevarious diseases," Disney noted in a press release. "Our new compound targetsthe toxic RNA and inhibits protein binding, shutting off the toxicity. Sincethe development of drugs that target RNA is extremely challenging, thesestudies can open up new avenues to exploit RNA drug targets that cause a hostof other RNA-mediated diseases."
Disney says that the team has been able to "design andoptimize a compound for biological activity that targets the CAG repeats inHuntington's disease and then reverses one of the defects that's been mostrecently associated with the disease in patient-derived cells." They have alsodesigned a compound that targets the triplet repeat present in myotonicdystrophy, an incurable form of muscular dystrophy, with the compounds provingto be bioactive in both cell models and animal models when it comes toreversing defects. Repeating RNA defects appear in a variety of other diseasesin addition to Huntington's and myotonic dystrophy, such as Fragile X syndrome.In addition, it has recently been discovered that there is a correlationbetween people with Lou Gehrig's disease, also known as ALS, and a GGGCCrepeat, Disney adds.
"The number of diseases that are caused by these repeatingRNAs, I think, is expanding considerably, if not exponentially," he says.
The work is far from over, Disney notes, as the team alreadyhas plans for how to further its discoveries. 
"What we need to do next—I think this is where the realimpact in making a therapy against Huntington's disease is—is we want to take thiscompound and try to use it as a lead to stop translation of toxic proteins," hesays. "Huntington's repeat is a CAG repeat, but it's in a messenger RNA thatgets made into protein. And so the next thing we want to do is not only shutoff the toxicity of the RNA but stop that RNA's ability to be translated into aprotein. 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 ScrippsResearch, with other authors including Raman Parkesh and Jessica Childs-Disney,both of Scripps Research, and Lukasz J. Sznajder and Krzysztof Sobczak of AdamMickiewicz University in Poland. Support for the study came from the NationalInstitutes of Health, the Polish Ministry of Science and Higher Education, Camille& Henry Dreyfus Foundation and the Research Corporation for ScienceAdvancement.
Camille & Henry Dreyfus Foundation
Research Corporation for Science Advancement

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