High efficiency platform for rapid RNAi rat model development

Abstract The cost of drug development has skyrocketed to an estimated $B for every FDA approved drug primarily due to failures from lack of efficacy or safetysuggesting that our current preclinical validation process has been insufficient in predicting therapeutic potential and toxicity in humansAnimal models are the gold standard for dissecting disease mechanisms and evaluating novel drug targets in vivohoweverthe cost and long lead time to develop them has prevented their routine use in the drug discovery processWith the recent developments in CRISPR Casgenome editingand advances in RNA interference technologieswe now have the ability to rapidly develop animal models with precise genomic modificationsand human like disease pathologiesWe have shown that RNAi serves as a fast alterative to gene deletion and can also be used within genetically engineered mouse models to assess the therapeutic potential and predict toxicities of novel gene targetsThe goal of this proposal is to expand our capabilities beyond mice and develop a platform for rapid and cost effective production of RNAi rats in as little asmonthsDespite the utility of mouse modelsfor many scientiststhe rat still remains the preferred rodent due to their larger size for surgical manipulationrepeat blood samplingand their cognitive and physiological characteristics that more closely resemble humans than their mouse counterpartsFor neurobiologycardiobiologyimmunology and toxicologythey are still the dominant rodent model in researchNearlyof our current client base has inquired about rat models over the lastyearsnoting that most toxicology studies of their compounds are still done in rats prior to Phase IWe believe that rats will gain popularity once again as the premier rodent model in drug discovery and we intend to be at the forefront of this shifting paradigmCRISPR Casgenome editing now provides a path for manipulating the rat genomehowevercurrent approaches enable the derivation of permanent gene knockout allelesbut do not allow temporal and reversible gene regulationOur goal is to draw from our vast experience of mouse model creation and exploit the efficiency of CRISPR based targeting to develop RNAi rat models that enable inducible and reversible gene silencing to simulate therapeutic regimesThese RNAi rat models will transform the preclinical validation process with assessment of potential drug response and resistance mechanisms in vivoultimately guiding the development of safer and more effective drugs Narrative The goal of this project is to develop a powerful and highly efficient platform for generating RNAi rat models with reversible gene silencing capabilities in as little asmonths using CRISPR mediated genome engineeringFor many scientiststhe rat still remains the preferred rodent due to their larger size and cognitive and physiological characteristics that more closely resemble humans than their mouse counterpartshowever current approaches of genome manipulation in rats allow for only permanent gene knockoutThrough temporal and reversible gene regulationthese RNAi rat models will transform the preclinical validation process with in vivo assessment of potential drug responseultimately guiding the development of safer and more effective drugs