RNA-based molecules have redefined the universe of
tractable targets by putting virtually anything that is gene encoded within
reach of a disease-modifying agent. This redefinition has launched RNA as the
biotech industry's third drug modality.
There has been a steady increase in investment in
oligonucleotide-based therapeutics over the past three years, including a surge
early this year (see "2014 first-quarter industry activity in RNA therapeutics").2
The discovery that the majority of the genome is expressed
as noncoding RNA was a major-and unexpected-finding from ENCODE.
Although the chemistry for noncoding RNA therapeutics is
on solid ground, the best way to find good targets is open to debate, and their
importance cannot be overstated.
emergence of lncRNAs
miRNAs already form the basis of a number of preclinical programs, lncRNAs are
a step behind as less is known-and much is debated-about how they affect
Looking out for orphans
To build a successful therapeutic program, the panel
recommended focusing on orphan indications that have been genetically validated
in humans in which using RNA could provide an advantage over competing
Identifying animal systems that faithfully model lncRNAs
in human disease is going to be difficult. Noncoding RNAs are not well
conserved across species, which will hamper the validation of lncRNAs as
Getting nucleic acid therapeutics into many types of
tissue remains a significant challenge for the entire field of RNA
therapeutics. Although chemical modifications stabilize RNAs for circulation,
rerouting the molecules away from being cleared by the reticuloendothelial
system and getting them across cell membranes remains difficult.
As an outside-the-box approach to solve the delivery
hurdle, the panel briefly discussed the use of nucleic acids ex vivo.
In addition to using delivery to increase the diversity of
accessible cell and tissue types, the panel said that delivery technologies can
help increase the amount of drug that reaches intracellular target RNA. Indeed,
panelists called for dedicated efforts to uncover ways of enabling escape of
delivered therapeutics from endosomes or lysosomes.
Raising the bar in preclinical research
The panel repeatedly emphasized the importance of robust
validation, establishing both that modulating the target can affect disease and
that a given therapeutic candidate acts specifically through the target (see
Box 2, "Considerations for compelling target and therapeutic validation").
Donner, A. SciBX 7(28); doi:10.1038/scibx.2014.815
Published online July 24, 2014
1. Kotz, J. SciBX 5(45);
2. Donner, A. SciBX
3. Wahlestedt, C. Nat.
Rev. Drug Discov. 12, 433-446 (2013)
4. Donner, A. SciBX
5. Reebye, V. et al.
Hepatology 59, 216-227 (2014)
6. Zhao, X. et al. Nat.
Neurosci. 16, 1024-1031 (2013)
7. Fishburn, C.S. SciBX
8. Yang, L. et al.
Nature 500, 598-602 (2013)
9. Cain, C. SciBX 6(34);
10. Hung, G. et al. Nucleic
Acid Ther. 23, 369-378 (2013)
11. Dong, Y. et al. Proc.
Natl. Acad. Sci. USA 111, 3955-3960 (2014)
12. Aleku, M. et al. Cancer
Res. 68, 9788-9798 (2008)
13. Donner, A. SciBX 7(10);
14. Gilleron, J. et al.
Nat. Biotechnol. 31, 638-646 (2013)
15. Haas, M.J. SciBX 7(3);
16. Fishburn, C.S. SciBX
AND INSTITUTIONS MENTIONED
Alexion Pharmaceuticals Inc. (NASDAQ:ALXN), Cheshire, Conn.
Alnylam Pharmaceuticals Inc. (NASDAQ:ALNY), Cambridge, Mass.
Apeiron Biologics AG, Vienna, Austria
Arrowhead Research Corp. (NASDAQ:ARWR), Pasadena, Calif.
Benitec Biopharma Ltd. (ASX:BLT), Sydney, New South Wales, Australia
City of Hope,
Dicerna Pharmaceuticals Inc. (NASDAQ:DRNA), Watertown, Mass.
Harvard Medical School, Boston, Mass.
Howard Hughes Medical Institute, Chevy Chase, Md.
Isis Pharmaceuticals Inc. (NASDAQ:ISIS), Carlsbad, Calif.
The Johns Hopkins University School of Medicine, Baltimore, Md.
Life Technologies Corp., Carlsbad, Calif.
Marina Biotech Inc. (Pink:MRNA), Bothell, Wash.
Massachusetts General Hospital, Cambridge, Mass.
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
San Diego, Calif.
Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J.
MiNA Therapeutics Ltd., London, U.K.
miRagen Therapeutics Inc., Boulder, Colo.
Moderna Therapeutics Inc., Cambridge, Mass.
National Human Genome Research Institute, Bethesda, Md.
National Institutes of Health, Bethesda, Md.
Opko Health Inc.
(NYSE:OPK; Tel Aviv:OPK), Miami, Fla.
Prosensa Holding N.V. (NASDAQ:RNA), Leiden, the Netherlands
RaNA Therapeutics Inc., Cambridge, Mass.
(Euronext:SAN; NYSE:SNY), Paris, France
Sarepta Therapeutics Inc. (NASDAQ:SRPT), Cambridge, Mass.
Silence Therapeutics plc (LSE:SLN), London, U.K.
University of California, San Diego, La Jolla, Calif.
The University of Texas MD Anderson Cancer Center, Houston, Texas
The University of Texas Southwestern Medical Center, Dallas, Texas