Synergistic treatment of macular disease using multivalent RNA nanoparticles

Age-related macular degeneration (AMD), a disease that gradually destroys central vision, is the leading cause of vision loss worldwide. The etiology of macular degeneration is not completely understood. This proposal aims to explore a new paradigm for the treatment of macular diseases using small RNA. An ideal therapeutic nanoparticle would be capable of passing the barriers within the retina, provide specific recognition of macular cells, penetrate into cells, carry multiple therapeutic agents and not be pathogenic. We will employ the phi29 motor pRNA as a delivery vector through simultaneous delivery of multiple therapeutic molecules. Phi29 packaging RNA (pRNA) has a tendency to form multimers through the interaction of interlocking loops. Insertion of molecules such as siRNA at their paired ends does not interfere with multimer formation. We propose to construct trimeric pRNA containing functional groups for specific recognition of cells in the macula and specific therapeutic functions such as siRNA, miRNA, or drugs. Our short term goals are 1) determination of the optimum size of RNA nanoparticles capable of reaching cells in the retina; 2) construction of multivalent RNA nanoparticles using therapeutic RNA targeting at multiple sites of one gene or multiple genes within a macular cell. The multiple components carried by the RNA should allow for treatment using low dose reagents on target cells for AMD.