Engineered Lipid Nanoparticle miRNA-therapy Options for ARDS

Severe and acute respiratory distress syndrome (SARS/ARDS) is an important and costly medical problem, for which there are few, or no treatments. In the case of COVID-induced SARS, steroids and immune modulating drugs may not be effective for all and have important side-effects. Having new treatments for ARDS/SARS would significantly reduce suffering and unburden the health-care system. We have discovered new roles for two microRNA (miR) - small RNAs that regulate protein levels. miR-193b-3p is increased in SARS/ARDS and it acts to disrupt 2 proteins that are important for the function and defense of the lung: (1) Occludin - contributes to cell function and prevents fluid from flooding the airspaces during virus or bacterial severe infections. (2) Surfactant protein C - prevents airspaces from collapsing during breathing. Both of these proteins are also involved in interacting and killing of pathogens or preventing their dissemination, and modulating immune responses. The second is miR-187a-3p. This miR is usually abundant in healthy individuals, but its levels fall during illness. miR-187a-3p is anti-inflammatory and it acts by decreasing levels of inflammatory mediators Tumor Necrosis Factor alpha and interleukin 6 - very important in SARS/ARDS. To translate our new research to humans, we have made two lipid nanoparticle (LNP), similar to the ones used for the Moderna and Pfizer vaccines. One contains and inhibitor of miR-193b-5p and the other a mimic of miR-187a-3p. In pilot animal studies, we delivered these medications in the blood through an intravenous injection. We show they reach the lungs and reduce the severity of ARDS without causing harm. Here we want to advance our work towards developing these therapies. An important step is to study them for thoroughly in animal models. We propose to use three models of ARDS - caused by influenza virus, bacteria and COVID virus. If successful, our work may lead to a novel treatment for ARDS.