MDRNA Successfully Silences Gene Targets in Animal Models Using UsiRNA Constructs
News Feb 24, 2009
MDRNA, Inc. has announced positive in vivo efficacy data on its proprietary UsiRNA constructs demonstrating a dose response which resulted in up to 90% knockdown of ApoB message in a rodent model.
The data were presented by Michael V. Templin, Ph.D., Vice President, Discovery Research and Pharmaceutical Development of MDRNA, at the inaugural Informa Life Sciences TIDES Oligonucleotide and Peptide® Research, Technology and Product Development Conference in Tokyo, Japan.
"Our UsiRNA constructs offer a novel and proprietary means of providing highly potent siRNAs while increasing specificity," stated Barry Polisky, Ph.D., Chief Scientific Officer of MDRNA.
"UsiRNAs were highly active in the mouse ApoB model for both message inhibition and serum cholesterol reduction. In these cases, UsiRNAs were fully compatible with RNAi machinery yet showed a substantial decrease in cytokine response. We are encouraged by these significant results and believe we have a unique siRNA construct to silence genes while minimizing potential side effects."
UsiRNAs are duplex siRNAs that are modified with non-nucleotide acyclic monomers, termed unlocked nucleobase analogs (UNA), in which the bond between two adjacent carbon atoms of ribose is removed. UsiRNAs are fully recognized by the RNAi machinery and provide for potent RNAi activity. Placement of UNA within UsiRNA minimizes the potential for off-target effects by the guide strand as well as undesired activity of the passenger strand. Further, the change in sugar structure renders this unlocked nucleobase analog conformationally flexible. The flexibility of the monomer escapes the surveillance mechanisms associated with cytokine induction, as well as providing protection from nuclease degradation.
"We are pleased to announce that our proprietary DiLA2 Platform achieved knockdown of two additional genes in liver tissue, DGAT2 and PCSK9, that are potentially important therapeutic targets, and the Platform continues to demonstrate safe and effective delivery following repeat systemic dosing of up to 9 mg/kg of siRNA formulations in mice," added Dr. Polisky.
"The acute and repeat dose tolerability data of the DiLA2 Platform are promising. Repeat dosing on an every-third-day schedule for two weeks further indicates that DiLA2 liposomes are well tolerated. Our ability to deliver siRNAs to hepatocytes while achieving knockdown of multiple gene targets affirms our belief that the DiLA2 Platform represents a significant advancement in the development of a novel formulation for improved siRNA delivery."