A report in The Lancet this week describes an
important milestone in the evolution of siRNA oligonucleotides as therapeutic
agents (1). PCSK9 is a protein that binds to and causes degradation of the Low Density
Lipoprotein-Receptor that is involved in cholesterol regulation. Patients with
mutations in PSCK9 have increased LDL-R and very low levels of blood
cholesterol thus validating the importance of this protein. Researchers at
Alnylam Pharmaceuticals have developed a siRNA that triggers destruction of the
messenger RNA for PCSK9 and have tested it in a small clinical trial. The siRNA
was delivered to liver cells (where PCSK9 is made) using a lipid-based
nanoparticle. The study showed a substantial reduction in PCSK9 levels and
corresponding decreases in serum cholesterol. Effects were seen with doses of
siRNA in the 0.15 mg/kg range, quite a low dose for this type of molecule.
The eventual intended use of
the PCSK9 siRNA would be in patients refractory to statins, the drugs commonly
used to reduce cholesterol. Apparently there are quite a few such patients
since by some estimates there is a $4B yearly market in this area. The siRNA
drug will have competition from anti-PCSK9 monoclonal antibodies that are
undergoing clinical testing by other companies.
Single stranded antisense
oligonucleotides can also trigger destruction of messenger RNA, although by a
different mechanism than siRNA. There are competing views on whether antisense
or siRNA offers the superior approach for new drug development. An antisense
oligonucleotide was recently approved by the FDA (2). Interestingly, this agent
is also designed to regulate cholesterol in statin-refractory patients but works
by reducing expression of a key component of LDL itself.
In both of these cases, the
target of the oligonucleotide drug was in the liver. This highlights a key
problem in the development of antisense or siRNA as therapeutic agents. It is
very difficult to deliver adequate amounts of these types of molecules to any
tissue other than the liver. While there
are certainly many liver-associated diseases that might be approached with this
technology, it would be a great step forward if efficient delivery to other
tissues could be attained.
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