Much attention has been paid to double-stranded RNAs in the last few years, and there is a growing consensus about the challenges in the field, namely delivery and off-target effects, notes Henrik Ørum, Ph.D., vp and CSO at Santaris Pharma. “As with new technologies, those issues are not easily solved. We’ve had significant interest in our locked nucleic acid (LNA) single-stranded format, as there are no issues with delivery and off-target effects as those seen with double-stranded RNAs.”
The LNA drug platform creates synthetically modified chemical versions of the normal nucleic acid building blocks of RNA. These modified chemical versions improve the drug-like qualities of resulting oligonucleotides by improving affinity to their target RNA, boosting resistance to metabolism, and improving tissue uptake. On systemic administration of these “naked” molecules, LNA-based therapeutics are delivered to their targets where they show efficacy as well as safety.
The company’s work with drug candidate SPC3649 will be presented at the conference, it was also published in Science in December. Dr. Ørum notes that SPC3649 targets and inhibits the liver-specific microRNA-122, which is required for hepatitis C virus (HCV) replication.
“Unlike many other therapies for HCV, SPC3649 works by targeting a host factor in the liver that the virus needs to replicate,” adds Dr. Ørum. “Targeting a host factor rather than attacking the virus directly has significant implications as it may reduce the risk of the virus becoming resistant to therapy, which remains a major concern for current therapies.”
According to Dr. Ørum, SPC3649 provided continued efficacy in animals up to several months after the treatment period with no adverse events and no evidence of viral rebound or resistance. “The preclinical data show changes in the expression of key genes that may help patients who do not respond to interferon treatment to become responsive. This could be a real game-changer for the treatment of patients infected with HCV.”