1180-P: Development of “Smart mRNAs” that Synthesize Corrective Proteins during Abnormal Metabolic States

Abstract

Diabetes and related disorders are associated with abnormal cellular metabolism, abnormal levels of various intracellular metabolites, and most importantly, impaired cellular responses which would normally correct these abnormalities. As a result, various tissues, such as liver, adipose, and skeletal muscle, exhibit altered cellular signaling and physiologic responses, which ultimately lead to the clinical signs and symptoms of diabetes. A major goal of synthetic biology is to develop new gene therapy approaches in which proteins are expressed in disease-affected tissues to correct these diverse metabolic abnormalities. However, a major challenge is to develop approaches in which the corrective proteins are only expressed when the cells exhibit metabolic derangements. Here we describe the first "smart mRNAs." These are mRNAs that can be expressed using standard gene therapy approaches, but are only translated when specific diabetes-associated metabolites are present. We describe how the 5' untranslated regions in mRNAs can be designed so that they bind diabetes-associated metabolites, and subsequently induce the translation of the encoded protein. We demonstrate the translational control that can be achieved with this new class of mRNA in various cell types, and we show how translation can be regulated by various metabolites and signaling states associated with diabetes. Lastly, we discuss how smart mRNAs can be used therapeutically in animal models in order to develop organs with restored cellular and signaling functions. Disclosure S. Jaffrey: Stock/Shareholder; Self; Gotham Therapeutics, Lucerna Biosciences. Funding American Diabetes Association/Pathway to Stop Diabetes (1-18-VSN-02)