In response to viral infection of a plant, a specialized RNA silencing system, cleaves, amplifies and trafficks 21-24 nucleotide fragments of viral RNA throughout the plant. This institutes a fascinating systemic and virus-specific response. In mammals, historically, RNA was believed to be restricted by the borders of individual cells. We demonstrated that vesicles secreted from cells, called exosomes, have specialized interactions with miRNA complexes and contain RNA that is shaped by miRNA-mediated silencing (Gibbings et al. Nature Cell Biology, 11: 1143, 2009). While evidence accumulates that exosomes can traffick RNA between cells the physiological contexts (e.g. brain, fertilization, epithelial linings) where this is most relevant await discovery.

A widespread interest has since developed in using the RNA content of exosomes retrieved from blood, urine or other fluids, to diagnose disease in difficult to access organs, such as brain. Our discoveries (patent pending) have been adopted by Alnylam Pharmaceuticals to develop a diagnostic technology that is helping bring RNA silencing drugs successfully through clinical trials (Coelho et al., New England Journal of Medicine, 2013). Others have demonstrated that exosomes may have potential as drug delivery vehicles, overcoming the traditionally invincible blood-brain barrier. Our research aims to enable these uses of exosomes and understand their physiological functions. Major research directions include characterizing how specific RNA are selected for packaging into exosomes, the destiny of exosome-packaged RNA, and its potential role in neurodegenerative diseases. 

 

Drug delivery is a major hurdle to the use of many promising drugs, such as RNA silencing drugs. RNA silencing drugs can potently and specifically silence expression of genes that cause disease, but the inability to introduce these drugs into cells other than in the liver has severely limited their use. Very recent work in animal models demonstrated that exosomes  can efficiently deliver RNA silencing drugs into even the hardest to reach tissues, like brain. Unfortunately, it is challenging to put RNA silencing drugs into exosomes. We believe we have solutions to this problem. Working with a major pharmaceutical company we aim to use a natural transport system in the body, exosomes, to deliver drugs, including RNA silencing drugs. 

 

 

Representative Publications

Derrick Gibbings, Constance Ciaudo, Mathieu Erhardt and Olivier Voinnet (2009). Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nature Cell Biology, 11(9): 1143-1149.

 

Alfica Sehgal, Qingmin Chen, Derrick Gibbings, Dinah Sah, and David Bumcrot (2014). Tissue-specific gene silencing monitored in circulating RNA. RNA, 20:143-149.