RNAi

RNA interference (RNAi) is a naturally occurring, highly specific mode of gene regulation mediated by double-stranded RNA (dsRNA).  dsRNA molecules are typically processed into ~19-base pair fragments, termed short interfering RNAs (siRNAs), by the enzyme Dicer.  siRNAs are then shuttled into a cytoplasmic multiprotein complex called the RNA-induced silencing complex (RISC).  RISC uses one of the strands as a guide to search the resident population of messenger RNAs (mRNAs) for complementary sequences.  Base pairing between the siRNA and the target sequence then leads to the down-regulation of the expression of the targeted mRNA by any of several pathways. 

SomaGenics' HCV lead

SomaGenics’ HCV lead abolishes gene-specific expression in liver.

RNA schematic
The mechanism of RNA interference

Since its discovery, RNAi has been used successfully in a wide range of studies on gene function, pathway mapping, drug target validation, and host-pathogen interactions. As therapeutics, siRNAs have entered or are approaching clinical trials for several disease indications. As was the case with antisense-based therapeutics, delivery of efficacious amounts of siRNA has proven challenging.

To meet this challenge, SomaGenics’ strategy has been to:

  • Focus on the most accessible organs for delivery, beginning with the liver, the target organ for HCV
  • Directly deliver shRNAs without relying on vector-driven gene therapy
  • Develop proprietary, highly potent shRNAs (to 5 picomolar IC50) so that even suboptimal delivery can provide a therapeutic level of the drug
  • Stabilize our lead shRNAs using proprietary modifications where necessary to improve their pharmacological properties
  • Assess all available delivery technologies for their ability to deliver RNA to the appropriate tissue for the indication of interest

 

References:

  1. Wang, C. H. Contag, H. Ilves, B. H. Johnston, and R. L. Kaspar,  Small hairpin RNAs efficiently inhibit hepatitis C IRES-mediated gene expression in human tissue culture cells and a mouse model. Mol. Therapy, 12:562-8 (2005). PMID 15953767
  2. A. A. Seyhan, A. V. Vlassov, and B. H. Johnston (2006) RNA interference from multimeric shRNAs generated by rolling circle transcription.  Oligonucleotides 16: 353-363. PMID 17155910
  3. A.V. Vlassov, B. Korba, K. Farrar, S. Mukerjee, A. A. Seyhan, H. Ilves, R. Kaspar, S. A. Kazakov, and B. H. Johnston (2007) shRNAs targeting hepatitis C: effects of sequence and structural features, and comparison with siRNA. Oligonucleotides 17:223-236. PMID 17638526
  4. Qian Wang, Heini Ilves,  Pauline Chu,  Christopher H. Contag, Devin Leake, Brian H. Johnston, and Roger L. Kaspar (2007)  Delivery and inhibition of reporter genes by small interfering and hairpin RNAs in a mouse skin model. J. Invest. Dermatol. 127(11):2577-84; Epub May 24, 2007. PMID 17522708
  5. R. P. Hickerson, A. V. Vlassov, Q. Wang, D. Leake, H. Ilves,  C. H. Contag, B. H. Johnston, and R. L. Kaspar (2008) Stability study of unmodified siRNA and relevance to clinical use.  Oligonucleotides 18(4):345-54; Epub Oct. 10, 2008. PMID 18844576