In an important new study with implications for the
treatment of dozens of incurable diseases, scientists from
the Florida campus of The Scripps Research Institute (TSRI)
have for the first time created a drug candidate that
attacks and neutralizes the RNA structure that causes an
incurable progressive, inherited disease involving a
gradual loss of control over body movement.
Matthew Disney is a professor on the Florida campus
of The Scripps Research Institute.
The study, which was published June 1, 2016 in Nature
Communications, showed the compound significantly
improved several aspects of cells taken directly from
patients with spinocerebellar ataxia type 10 (SCA10), a
form of spinocerebellar ataxia.
“More than 30 diseases, all of them incurable, are caused
by RNA repeats,” said TSRI Professor Matthew Disney, who
led the study. “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’s like the
defect is not even there.”
SCA10 is caused by what is called a pentanucleotide repeat
(a genetic sequence of five nucleotides repeated many more
times than normal) affecting the mitochondria, the cell’s
energy source. The new drug candidate, known as 2AU-2,
targets these repeats by binding to RNA base pairs.
“The potent bioactivity of 2AU-2 to moderate the
structurally induced toxicity in SCA10 strongly suggests
that base-pair-targeting RNA modules could have broad
applicability in our effort to develop other compounds that
target different RNAs,” said TSRI Research Associate
Wang-Yong Yang, the first author of the study. “More than
70 percent of RNA secondary structure is made up of base
The Disney group has developed new tools to identify
optimal interactions between RNA structures and drug
candidates targeting them. A database of these interactions
has already been used to design several small molecule drug
“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. That environment
can contain millions of other RNAs. In this study,
Wang-Yong has done an exceptional job tackling this
previously-thought-to-be-impossible molecular recognition
problem,” Disney said.
Pathogenic RNA repeats contribute to disorders including
Huntington’s disease, fragile X-associated tremor ataxia
syndrome and myotonic dystrophy type 1 and 2.