siRNA Delivery Vehicles for Systemic Administration

• Novel polymers and lipids for encapsulation
• Low toxicity and biodegradable
• Amenable to use of process development & manufacturing platforms
• Amenable to molecular targeting strategies
• Long-term storage stability
• Delivery Vehicles that improve endosomal escape

siRNA Sequence, Structure, and Modification

• Novel chemistries for improving resistance to enzymatic degradation
• Novel chemistries for reducing immunostimulation
• Enhanced RISC incorporation
• Long-term chemical stability
• Improved target specificity

Approaches to Molecular Targeting of siRNA

• Targeting using antibodies, peptides, or small molecules
• Specific for disease-relevant cell types
• Suitable for nanoparticle or liposome delivery

Assays for siRNA Intracellular Functions

• Assays for siRNA endosomal escape
• Biochemical assays for strand selection, RISC incorporation,
  catalytic efficiency
• Assays for clinical biodistribution
• Cell-based assays to measure Toll receptor activation

Validated siRNA Targets

• Demonstrated reduction in mRNA and protein levels in animals
• Reductions have expected effect on disease phenotype

miRNA

• Novel chemistries to create antagomirs
• Demonstrated reduction of miRNA levels in animals, with evidence that reductions have expected effects on mRNA levels and/or disease phenotype
• Demonstrated delivery of miRNA in animals, with evidence that increases in miRNA have expected effects on mRNA levels and/or disease phenotype

RNA Manufacturing

• Advancements in large-scale production of modified siRNA
• Improved processes for increased quality, efficiency, and reduced COG
• Novel chemistries
• Universal linker based solid support for production of siRNAs
• Robust LC-MS method for determination of impurity profile of phosphoramidite raw materials and oligonucleotides (siRNAs)

Information Technology

• Registration and tracking of information related to complex multi-component biologics