Design:
Using a proprietary algorithm for siRNA sequence prediction against gene target of interest, we can rapidly identify siRNA sequences with Seven characteristics including (1) optimal thermodynamics, (2) enhanced RISC binding, (3) eliminated (or added) immune stimulating motifs, (4) minimized “Off-Target” potential, (5) having homology between human and mouse sequences (to facilitate ease of development), (6) patent searched and (7) no interaction when multiple sequences mixed in the cocktail. The individual siRNA sequences and their combinations allow unique composition of matter patent protection. A web-based operation system as shown on right allows rapid design of siRNA sequences targeted the gene of interest. The siRNA duplexes can be 21, 23, 25 and 27 mer in length with either blunt or sticky ends.

Delivery:
Sirnaomics delivery technologies allow selection of the best approach to ensure efficient and safe delivery of siRNAs to their target tissues. Three generations of nanoparticle systems for siRNA delivery at various stages are being developed.

(1) First Generation Nanoparticles:

Our first generation of delivery agents uses clinically viable and clinically approved nanoparticle technologies for use as siRNA delivery vehicles in vivo. These include polymer and liposome-based carriers for siRNA therapeutic applications. Some of these materials may best be suited for delivery through specific routes of administration e.g. through inhalation to allow access to the lung or via systemic delivery to target a tumor through the EPR effect.

• SNANO-1 is a branched cationic polymer for enhanced siRNA delivery in vivo.

• SNANO-2 is a clinically validated Dendrimer for delivery of siRNA in vivo.

• SNANO-3 is a clinically approved PLGA for delivery of therapeutic agents including siRNA.

• SNANO-4 is a Pegylated cationic polymer for local delivery of siRNAs in vivo.

• SNANO-5 is a liposomal carrier for siRNA delivery in vivo.

• SNANO-6 is a Pegylated Spermine nanoparticle for siRNA delivery in vivo.

(2) Second Generation Nanoparticles:

The chemical modification and protection of the first generation of the nanoparticle, and fictionalization of the vector with the Ligand-directed tissue targeting nanoparticles resulted in the 2nd generation of the nanoparticle for siRNA in vivo delivery. Such ligands are ranging from small molecules, monoclonal antibodies and peptides, for tissue and cell type specific siRNA delivery. The target tissues currently being explored include the tumor, lung, liver and brain as well as the development of materials that can cross the blood brain barrier and those that can migrate across the skin.

(3) Third Generation Nanoparticles:

Temporally and locally controlled delivery systems with infrared activated siRNA and photodynamic therapeutics: a silica-coated upconversion nanoparticle equipped with ligand-directed targeting has been developed for siRNA systemic and local delivery. The nanoparticle can release siRNA in response to an external trigger (near infrared) and has features that may be especially suited for treatment of solid tumor in deep body like liver, renal, pancreas and lung cancer.

Human diseases are often complex syndromes involving contributions from multiple genes. To address this aspect of human disease etiology and to take advantage of the chemical simplicity (uniformity) of siRNA design, a proprietary algorithm allows development of a “Tri-Blocker” design of a cocktail of siRNA duplexes targeting up to three disease-causing genes in one drug API. The siRNA API validated in cell culture is further tested and validated in a suitable animal model for its therapeutic properties using our efficient in vivo siRNA delivery systems. The specific siRNA cocktail and appropriate siRNA delivery system can be combined to address the particular disease. The mouse-human homology of selected siRNA APIs allows direct translation from target gene knockdown in the animal model into future human clinical testing.