Systemic siRNA passes safety milestone
Images courtesy of Alnylam
Researchers from Alnylam Pharmaceuticals, Roche Kulmbach, the Swiss Federal Institute of Technology, UT Southwestern Medical Center at Dallas, and MIT have collaborated on research published online yesterday in Nature (subscription req.) that demonstrates the efficacy and afety of systemically administered synthetic siRNA.
Despite the hype that has followed siRNA for the last couple of years, accompanying the IPOs of SIRNA Therapeutics and Alnylam Pharmaceuticals, many unknowns remain about the feasibility of delivering systemic synthetic siRNA safely and effectively. For siRNA proponents and their investors, one of the scariest unknowns was whether siRNA would suppress microRNAs. microRNAs are ~22nt RNAs that regulate transcription and translation of proteins via a protein complex. known as RISC. Unlike siRNA, which generally suppresses a single mRNA transcript, microRNAs each affect the regulation of more than one protein, providing a post-transcriptional mechanism for coordinated regulation of important cell growth and survival pathways.
The concerns regarding siRNAs were brought to light last year, when it was discovered that systemic delivery of synthetic short hairpin RNAs (shRNAs, natural precursors to siRNA) disrupted microRNA synthesis, leading to frequent fatal toxicity. The cause of toxicity was believed to be saturation of a protein needed for nuclear export of microRNA precursors. Although it was believed that siRNAs would not cause the same saturation problem, it was not known for certain whether in vivo concentrations of siRNA sufficent to suppress mRNA by upwards of 80% would avoid similar microRNA disruption and its associated toxicity. This latest work shows that siRNA administration leading to therapeutic effects is not associated with microRNA suppression or severe toxicity in mice. Because these pathways are largely evolutionarily conserved, it’s expected that the findings will be transferable to humans, although no studies of systemic siRNA administration to humans have been conducted. Non-human primates have been administered siRNA systemically, with promising results so far.
Bottom line is that this work was a necessary and important step in the progression of systemic siRNA therapy for humans. Both Alnylam and Sirna (now a part of Merck) are testing synthetic siRNAs delivered locally into the airways and eyes, respectively. Both also have siRNAs intended for systemic delivery in preclinical testing. We can now be reasonably assured that both firms will eventually advance systemic siRNAs into the clinic. Although the first clinical disease targets for systemic siRNA aren’t known for sure, decent bets for Alnylam are hypercholesterolemia and liver cancer, and for Merck are Hepatitis C and Type 2 diabetes.
