As an increasing number of DNA and RNA-oligonucleotide-based drugs are moving through clinical trials, the pharmaceutical industry is focusing on ways to bring these novel therapeutics to market at a competitive prices. The primary goal of this project is to help reduce the cost of producing oligonucleoside-based drugs, via a novel synthesis solid support. It has been noted by leaders in the industry, that solid support-related costs are a major factor in large-scale oligonucleotide production. (1). Aside from lowering the cost of the solid support itself, one way to gain economy is to increase the oligonucleotide yield per unit volume of solid support - primarily through higher initial nucleoside loadings. Improving the scalability characteristics of the solid support, so that larger batch sizes of oligonucleotides could be produced would also enhance economy. A solid support designed to improve oligonucleotide purity would result in less costly production via less purification costs. At larger pore sizes (>600 Angstroms), Controlled Porosity Glass (CPG) is often the preferred solid support for large scale syntheses of RNA and longer oligos (2), however it's maximum nucleoside loading capabilities are somewhat limited. Porous polystyrene supports are available in much higher nucleoside loadings;however they cannot be used at these loadings for RNA and longer oligos, due to solvent swelling effects and related pore distortion. They do, however allow the use of certain synthesis reagents that can be corrosive to glass. By combining the large and dimensionally stable pore characteristics of CPG, with the higher loading capacities of polystyrene, a superior hybrid solid support should result. The product of this research will facilitate syntheses of the newer, bulkier therapeutic oligos with higher purities than polystyrene supports, with higher yields than CPG supports, yet will be rigid enough to scale to very large reactors without suffering from the compression and reduced synthesis solution flow characteristics that would limit solvated polymer supports. Preliminary attempts in this laboratory to produce such a hybrid support have been very encouraging.
As an increasing number of DNA and RNA-oligonucleotide-based drugs are moving through clinical trials, the pharmaceutical industry is focusing on how to bring these novel therapeutics to market at a competitive prices. The purpose of this project is to develop a novel solid support, which will provide a more cost-effective approach to the large-scale syntheses of such oligonucleotides.
