Abstract Autosomal dominant polycystic kidney disease (ADPKD) is amongst the most common monogenetic human disorders. Nearly 600,000 Americans are affected by this devastating condition. Unfortunately, treatment options are limited. To address this large unmet need, we will explore a novel therapeutic opportunity involving targeting the RNA chemical modification pathway. It has now become clear that, like DNA, RNA also undergoes dynamic chemical changes that impacts its processing and function. In preliminary analysis we found that mRNAs from cystic kidneys exhibit higher levels of a specific RNA modification called m6A, which refers to methylation of the 6th nitrogen in adenosine. Moreover, we noted that reducing m6A levels by deleting Mettl3, a key enzyme that mediates this modification, ameliorates preclinical PKD. Further mechanistic studies suggested a novel hypothesis that lowering m6A levels alleviates PKD by reducing translation of pathogenic mRNAs. Based on these promising observations, we propose to: (a) use complementary genetic and pharmaceutical approaches to conclusively validate the Mettl3/m6A pathway as new drug target in ADPKD. (b) Identify the m6A-regulated pathogenic proteome in ADPKD. In summary, RNA modification is an emerging field with broad implications in physiology and disease, yet its impact on kidneys is unknown. We are the first to address these fundamental knowledge gaps. Building on our strengths in RNA and ASO biology, we will also uncover a novel drug target for ADPKD.