Will RNAi-based therapeutics provide the next class of blockbuster drugs? If pharma’s acquisition spree of companies with relevant technologies proves predictive, then all bets are on. In 2001, siRNA duplexes were hailed as new tools for studying gene function in mammalian cells, and it was predicted that they eventually would be used as gene-specific therapeutics as well. The subsequent growth spurt in the use of RNAi as a research tool and potential drug target has borne out that prediction. Advancement toward the clinic, however, depends on overcoming some key hurdles, including drug delivery and off-target effects.
Technical hurdles notwithstanding, discovery of the RNAi gene-silencing process as a universal control mechanism in eukaryotes has prompted a major wave of consolidation as pharma and other companies devour the key enabling technologies, and continue to develop new ones.
RNAi’s potential as a drug target has attracted huge investments by pharmaceutical companies, as exemplified by Roche’s 2007 announcement that it had committed “over a billion dollars” to a deal with Alnylam Pharma. A year later, Roche acquired Mirus Bio for $125 million to expand its stable of technologies to enhance delivery and potential clinical use of siRNA.
AstraZeneca followed suit with a three-year R&D collaboration with Silence Therapeutics calling for that company to ultimately receive about $400 million for up to five siRNA-based drugs aimed at specific targets provided by AstraZeneca.
Key to the rapid growth of RNAi applications have been new tools and technologies that simplify its use, decrease its cost, and increase its accessibility in a wide variety of research settings. Strategies employed to activate the RNAi pathway and specifically silence genes include introduction of synthetic siRNA into cells or DNA vectors expressing short hairpin RNAs (shRNAs) or miRNAs.
RNA interference can also be achieved in mammalian cells using plasmids containing shRNA. As the field has advanced, so has the realization that multiple factors influence the success or failure of RNAi studies; chief among these are transfection method, transfection conditions, cell type, whether the cells are adherent and confluent or nonconfluent, or in suspension culture, the quality and quantity of siRNA, reagent toxicity, and in the case of in vivo and clinical studies, siRNA delivery.
Several companies are developing methods and reagents to address some of the major challenges in using RNAi-related technologies and potentially enable their use as therapeutic agents. Most view poor transfection efficiencies arising from a variety of conditions as a significant source of compromise to experimental results.