SomaGenics demonstrates that their short synthetic shRNAs function as a direct-acting anti-viral agent against Hepatitis C
SANTA CRUZ, Calif., May, 2014 SomaGenics’ short synthetic shRNAs (sshRNAs) inhibit Hepatitis C virus propagation in mice. Now Somagenics has published results showing that their therapeutic sshRNAs exert a direct effect on the viral RNA, causing mutations in the targeted viral RNA sequence. These results confirm a specific mechanism of action and establish sshRNAs as a novel class of direct-acting antiviral agents. Multiple sshRNAs can be combined to increase the selection pressure on the virus in order to reduce the development of treatment-resistant viruses.
Short synthetic shRNAs are small stem-loop (or hairpin) RNAs that knock down target RNAs through an RNA interference (RNAi) mechanism. In contrast to other RNAi mechanisms, sshRNAs induce the cleavage of target RNAs by a Dicer-independent mechanism. The described new experiments examined the evolution of the Hepatitis C virus (HCV) in response to treatment with sshRNAs.
HCV-infected chimeric mice that harbor human hepatocytes were treated with two different sshRNAs. The sshRNAs were designed to target different but overlapping regions in the IRES sequence, a conserved element of the viral RNA which is required for translation of RNA into proteins and therefore for virus proliferation. Virus RNA sequences were analyzed three weeks after completion of a two-week treatment of infected mice, when viral loads had decreased to below 90% of the pretreatment level. Sequence analysis revealed that almost all of the recovered viral RNAs had mutations in the region that was targeted by the respective sshRNA, but not in the surrounding RNA. Higher sshRNA doses triggered more mutations than lower doses. No mutations were found in the IRES region in response to treatment with a non-targeting sshRNA. This result confirms the direct mechanism of action of sshRNAs against viral RNA.
The induced mutations conferred viral resistance to the RNAi agents, causing a recovery of the viral load. The loss of sshRNA potency against the mutated virus populations was confirmed in cell culture experiments. A combination treatment with two different sshRNAs lead to increased mutation pressure on the virus population, explaining the more potent anti-viral activity of a combination approach. A comparison between the two employed sshRNAs revealed that the more potent agent caused 2 or 3 mutations whereas the less potent variant caused mostly single point mutations in the sshRNA binding site. These results directly indicate that the mutation pressure exerted by the sshRNAs on the virus lead to decreased viral load.
About Hepatitis C Virus
HCV is a leading cause of cirrhosis, liver cancer, and liver failure requiring liver transplant. An estimated 170 million people are infected with HCV globally, with 3-4 million new infections each year. No vaccine for HCV is currently available.
About RNAi and SomaGenics’ sshRNA Technology
The Nobel-prize-winning discovery of RNA interference (RNAi), a process by which double-stranded RNA molecules can inhibit the function of virtually any gene, has spurred interest in the development of short interfering RNAs as drugs. SomaGenics has pioneered the discovery and development of a unique class of short interfering RNAs called sshRNAs. Structurally distinct from the more commonly used siRNAs and expressed shRNAs, sshRNAs are short, chemically modified RNA sequences that are chemically synthesized as single strands. They have outstanding potency and possess attractive pharmacokinetic properties without undesirable immune stimulation.
About SomaGenics
SomaGenics is a privately held company that develops innovative RNA technologies for therapeutic and diagnostic uses. SomaGenics’ lead therapeutic program, against hepatitis C virus, has successfully completed efficacy evaluations in preclinical animal models and is ready for clinical development.
The citation for the paper is Dallas, Ilves et al., J Virol. 2014 May;88(9):4647-56. Aspects of the findings have been presented at the following scientific meetings:
June 2014
Nucleic Acid Research & Discovery conference, GTC, San Diego; Featured lecture by BJ.
May 2014
American Society for Gene and Cell Therapy Annual Meeting (ASGCT), Washington DC; poster presentation by BJ.
April 2014
Symposium of Viral Hepatitis, Varadero, Cuba; invited talk by BJ
March 2014
- International RNA Summit, UC Sant Cruz; invited talk by BJ
- MicroRNA as Biomarkers and Diagnostics Conference, Boston; invited talk by BJ and BJ moderated a Roundtable on Detection of Circulating microRNAs.
- University of Massachusetts Medical School; seminar by BJ
Upcoming presentations
July 2014
3rd International Conference on Gastroenterology & Urology, San Francisco, July 28-30, 2014; invited talk by BJ
November 2014
American Association of Pharmaceutical Scientists (AAPS) Annual Meeting, Workshop on Emerging Trends in Nucleic Acid and Cell-Based Therapeutics, San Diego; invited lecture by BJ