Experimental Drug Targets Diseases Caused by Toxic RNA Nucleotide Repeats

A small molecule drug designed to interact with defective RNA was shown to displace sequestered proteins and correct defects in cells derived from patients suffering from the incurable neuromuscular disorder spinocerebellar ataxia type 10 (SCA10).

SCA10 is characterized by slowly progressive cerebellar ataxia that usually starts as poor balance and unsteady gait, followed by upper-limb ataxia, scanning dysarthria, and dysphagia. The disease is exclusively found in Latin American populations, particularly those with Amerindian admixture. Abnormal tracking eye movements are common. Recurrent seizures after the onset of gait ataxia have been reported with variable frequencies among different families. Some individuals have cognitive dysfunction, behavioral disturbances, mood disorders, mild pyramidal signs, and peripheral neuropathy.


SCA10 is one of several disorders including Huntington's disease, fragile X-associated tremor ataxia syndrome, and myotonic dystrophy type 1 and 2 that are caused by repeated nucleotide RNA sequences. In SCA10 a pentanucleotide repeat disrupts mitochondria function. Currently, there have been no convenient means for correcting this type of RNA defect.

Investigators at The Scripps Research Institute (Jupiter, FL, USA) searched for small molecules that could selectively bind RNA base pairs by probing a library of RNA-focused small molecules.

They reported in the June 1, 2016, online edition of the journal Nature Communications that they had identified small molecules with benzamidine moieties that were able to bind selectively to AU (adenine-uracil) base pairs. Armed with this knowledge, the investigators synthesized a dimeric compound (2AU-2) that targeted the pathogenic RNA - containing expanded r(AUUCU) repeats - that causes SCA10 in patient-derived cells.

Treatment of SCA10-derived cells with 2AU-2 corrected various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of the enzyme caspase 3, and reduction of nuclear foci.

"More than 30 diseases, all of them incurable, are caused by RNA repeats," said Dr. Matthew Disney, professor of chemistry at The Scripps Research Institute. "By a thorough basic science investigation, we identified small molecules that target RNA base pairs precisely. We then leveraged this information to design the first drug candidate that binds to disease-causing defects in SCA10. Application of the drug candidate returns certain aspects of those cells to healthy levels – it is like the defect is not even there. We are in the process of developing tools that allow one to design small molecules to target any RNA structural motif in a complex cellular environment."

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