Alnylam, Mount Sinai scientists discover svRNAs that play a critical role in influenza A virus replication

Alnylam PharmaceuticalsJun 2 2010

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today the publication of new research findings in the journal Proceedings of the National Academy of Sciences (PNAS) by Alnylam scientists and collaborators from Mount Sinai School of Medicine. In the new study, Alnylam and Mount Sinai scientists discovered a novel class of virus-produced small non-coding RNAs, called small viral RNAs (svRNAs), which play a critical role in the replication of influenza A virus. Antagonism of these svRNAs resulted in decreased viral mRNA and blocked viral infectivity. These new findings provide further understanding of how influenza virus is able to infect cells, and identify new targets and strategies for anti-influenza virus-based therapies.

“a major scientific breakthrough that happens once every decade or so”

"The discovery of svRNAs that play a critical role in flu virus replication opens the door for the development of novel RNA therapeutics for the treatment of flu infection, an area of major unmet need," said Antonin de Fougerolles, Ph.D., Vice President, Research, Immunology, Metabolic, and Viral Disease at Alnylam. "As a leader in the field of RNAi therapeutics and the emerging understanding of the critical role RNA plays in biological processes, this new paper underscores Alnylam's unique position in translating these basic discoveries into novel medicines."

"Influenza is a major pathogen responsible for significant morbidity and mortality worldwide, including the threat of global pandemics. Today's anti-viral medicines are limited in their mechanism of action and by emergence of resistant flu strains," said Benjamin tenOever, Ph.D., Assistant Professor, Microbiology of The Mount Sinai Medical Center. "Our lab's interest in the biology of flu infection has led to the discovery of svRNAs that appear to control the switch from viral genome transcription toward viral replication. We are excited to work with Alnylam on RNA therapeutics targeting svRNAs as a new approach for anti-viral medicines."

The new research (Perez et al., Proc. Natl Acad. Sci. USA, doi: 10.1073/pnas.1001984107, 2010) describes the discovery of influenza A svRNAs and their role as part of a viral mechanism to control the switch between transcription and replication, representing a new paradigm in virus biology. svRNAs were found to mediate their activity by direct association with the viral RNA polymerase enzyme, representing a distinct mechanism of action as compared with other classes on small non-coding RNAs, such as microRNAs, which act by controlling gene expression through interactions with target mRNAs. Specifically, data from these studies showed that:

• influenza A infection results in the expression of svRNAs that range from 22 to 27 nucleotides in length and correspond to the 5´ end of each viral genomic RNA (vRNA) segment;
• expression of svRNA was found to correlate with the accumulation of vRNA and was found to be essential in converting RNA-dependent RNA polymerase (RdRp) activity from transcription toward genome replication;
  • in addition, svRNA was detectable during the shift from viral transcription to replication in a broad range of influenza A virus subtypes across multiple host species; and,
• the inhibition of specific svRNAs using chemically modified, single-stranded anti-svRNA oligonucleotides resulted in suppression of vRNA synthesis in a segment-specific manner and potently blocked viral infectivity.