Abstract

FolamiRs: Ligand-Targeted, Vehicle-Free microRNA Replacement Therapy

Andrea Kasinski, William and Patty Miller, Assistant Professor of Biological Sciences, Purdue University

MicroRNAs are small non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. Because elevations or reductions in microRNA levels can promote or maintain disease states, microRNA-based therapeutics are being evaluated extensively. Unfortunately, the therapeutic potential of microRNA replacement is limited by deficient delivery vehicles. In this work, we introduce a novel delivery platform that delivers microRNAs in the absence of a protective vehicle. The method relies on the direct attachment of a microRNA to folate (FolamiR). Folate mediates the delivery of the conjugated microRNA into cells that overexpress the folate receptor (FR), a feature commonly found in multiple cancers.  Using this strategy, we show that a specific tumor suppressive FolamiR, FolamiR-34a, is quickly taken up by human triple-negative breast cancer cells, in culture and in vivo, and slows their progression, and demonstrate efficacy in an aggressive Kras;p53 non-small cell lung cancer mouse model. These findings suggest that this first-in-class method of delivering microRNAs directly to tumors in vivo, without the use of toxic delivery vehicles, represents an exciting advance in the pursuit to develop non-toxic, targeted therapeutics with promising clinical efficacy.