o Drs. Andrew Fire and Craig Mello discover gene silencing mechanism (RNA interference) in October 2006; jointly awarded “The Nobel Prize in Physiology or Medicine for 2006.”
o Gene silencing mechanism is the ability to suppress the production of disease causing proteins associates with the discover of the function and role of individual genes
o First to rationally designed synthetic formulation for nucleic acid delivery that mimics the natural viral targeting and disassembly process
o Chemically synthesized to include the following functional elements:
§ Endosomolytic Polymer
§ Charge Masking Agents
§ Environmental Responsive Linkage Chemistry
§ Targeting Ligand (specific to the target cell or tissue)
§ Short interfering RNA Sequence (siRNA specific to a disease target gene)
o Keys to the success of this formulation are:
(1) the endosomolytic potency of the polymer
(2) the unique ability of the complex to respond to location-specific environmental cues
(3) efficient cellular targeting.
o Various targeting molecules including sugar or peptide based receptor-targeting ligands, monoclonal antibodies, or heavy-chain antibody fragments can be incorporated into the DPCs to target specific cell types
o When injected into the bloodstream, unmodified and unprotected siRNAs are rapidly degraded.
o Modifications /strategies ( to increase circulation half-life and functionality):
§ incorporation of stabilizing chemical modifications
§ encapsulating the siRNA in liposomes
§ attachment of a cholesterol group or common polymers to siRNA
o Mirus Bio Researchers discovered and patented a new class of polymers that provide a unique dual benefit. These polymers both impart superior functionality to the nucleic acid while in the bloodstream and promote highly efficient transport of the siRNA from the endosome into the surrounding cytoplasm in the target cell.
o Special features of DPC:
-- combine efficient targeted delivery
-- low toxicity
-- effective gene silencing
-- able to generate the predicted physiologic effect
o Currently being optimized for liver and cancer tissues
o Actively being evaluated by select partners for research and clinical indications
