May 30, 2018
Scientists at The Scripps Research Institute
have developed a small molecule-based RNA-editing tool that can selectively
delete RNA targets associated with diseases such as cancer. Offering a
potential alternative to CRISPR-Cas9–based tools that edit DNA, the new
technology, developed by Matthew D. Disney, Ph.D., attaches an RNA-targeting,
drug-like molecule to an RNA-degrading enzyme. Because the technology uses
small molecules rather than proteins, it could also feasibly be packaged into a
convenient oral pill.
Initial tests demonstrated that a
ribonuclease-targeting chimera (RIBOTAC) designed against a breast cancer
microRNA (miRNA) oncogene caused the death of malignant cells, without harming
normal cells. "I believe this is just the tip of the iceberg of how this
approach will ultimately be applied," says Dr. Disney. “Since it is now
known that RNA is a key driver in nearly every disease, optimization of this
approach that turns a cell's natural defenses toward destroying disease-causing
RNAs is likely broadly applicable.”
The Florida campus Scripps team reports its
findings in the Journal of the American Chemical Society,in a paper
entitled “Small Molecule Targeted Recruitment
of a Nuclease to RNA.”
While only about 2% of the genome encodes
proteins, 70% to 80% of the genome is transcribed into RNA, and this offers up
potentially far greater numbers of targets. However, RNAs have traditionally
been considered largely undruggable because of their small size and lack of
stability. The Disney laboratory has developed a computational method,
InfornaTM, that can match small, drug-like molecules with small,
stable RNA-binding partners. This technology led to the development in 2016 of
Targaprimir-96, which selectively binds with miRNA-96, a miRNA oncogene that
promotes cancer cell proliferation in cancer, including hard-to-treat
triple-negative breast cancer.
For their initial tests with the new
small-molecule RNA-targeting technology, Dr. Disney’s laboratory combined
Targaprimir-96 with RNase L as the RNA-degrading enzyme. RNase L is produced in
small amounts by all cells as part of the human antiviral immune response and
is upregulated to target viral RNAs during an infection. “A small molecule that
selectively binds the oncogenic microRNA(miR)-96 hairpin precursor was appended
with a short 2'-5′ poly(A) oligonucleotide,” the team explains.
When applied to cancer cells, the
RNA-targeting complex effectively destroyed the target oncogenic miRNA-96
molecule. “The conjugate locally activated endogenous, latent ribonuclease
(RNase L), which selectively cleaved the miR-96 precursor in cancer cells in a
catalytic and sub-stoichiometric fashion,” they wrote.
Destroying the miRNA-96 effectively unblocked
repression of the transcription factor FOXO1, which triggered the
triple-negative breast cancer cells to self destruct. “Silencing miR-96
derepressed pro-apoptotic FOXO1 transcription factor, triggering apoptosis in
breast cancer, but not healthy breast cells,” the authors write.
“Anchoring our previous work with
Targaprimir-96 to the targeted recruitment of RNase L, we were able to program
the RIBOTACs approach to only degrade cells that highly express the miRNA-96
oncogene, thus allowing FOXO1 to signal the selective destruction of
triple-negative breast cancer cells," comments Matthew G. Costales, a
graduate student in the Disney lab, and first author of the team’s published
paper. “These results demonstrate that small molecules can be programmed to
selectively cleave RNA via nuclease recruitment and has broad implications,”
the authors conclude.
“We will be laser-focused on diseases for
which there are no known cure and have a poor prognosis, such as hard-to-treat
cancers and incurable human genetic disease,” Disney comments. “I am excited to
see where we and others ultimately take this.”
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