Delivery of small-interfering RNA (siRNA) to the brain

Background: Two fundamental difficulties in the delivery of drugs to treat central nervous system (CNS) diseases are the systemic delivery of therapeutics across the bloodbrain-barrier (BBB), and the targeting of drugs to specific tissues or cells within the brain. With the advent and promise of RNA-based therapeutics that utilize RNA interference (RNAi) to trigger specific silencing of genes within diseased tissues, the necessity to surmount such obstacles has become even more urgent. Objective: Most pre-clinical and clinical studies on delivery of RNAi to the CNS have utilized invasive, intra-cerebral delivery of RNA to the targeted tissue. Thus, methods need to be developed to facilitate delivery of therapeutically significant quantities of RNA to the CNS via the systemic route, and to elicit clinically significant RNAi effects within the CNS tissues. Methods: Cell-penetrating-peptides (CPPs) are 'molecular delivery vehicles' that can traverse cell membranes and co-transport peptides or polynucleotides. The present invention examines 1) the utility of CPP-RNA duplexes for delivery of RNA to CNS tissues and, 2) cell-mediated release of the RNA payload once the CPP-RNA duplex is internalized by the CNS cells. Conclusions: The invention and embodiments listed therein outline molecular tools that can be adapted for non-invasive, systemic delivery of therapeutic RNA to the CNS in a future clinical setting.