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.