Grant: Project Grant

Autoimmune disease affects more than 20 million people in North America. Autoantibodies such as anti-Ro52 are present not only in autoimmune disease patients but also in 0.6-2.7% of the general population. In addition, monoclonal antibody drugs such as rituximab are a fast growing area of drug development with a multi-billion market. Emerging clinical evidence suggests that certain antibodies (e.g. anti-Ro52 and rituximab) can cause a heart electrical disorder called long QT syndrome, and cardiac arrhythmias. The rhythmic heartbeat is controlled by specialized proteins in the cell membrane called ion channels. Among them the potassium channel "hERG" is the common target for various medical conditions. Dysfunction of hERG is the primary cause of medical condition-induced long QT syndrome. We hypothesize that certain antibodies (e.g. anti-Ro52, rituximab) damage hERG function and thus cause long QT syndrome. Our project has three aims. 1. We will determine whether and which specific antibodies impair hERG function in hERG-expressing cell lines as well as in heart cells isolated from neonatal rats. 2. We will perform detailed investigation on how hERG function is impaired by antibodies using state-of-the-art biomedical techniques in hERG-expressing cell culture systems. We will also investigate novel strategies to prevent antibody-mediated impairment of hERG channels. 3. We will induce specific antibodies in a live rabbit model via immunization and verify the idea that the induced antibodies disturb the heart rhythm. We will investigate how to prevent antibody-mediated heart rhythm disturbances using biological and pharmacological approaches. This project reveals a novel cellular pathway that underlies antibody-mediated heart rhythm disturbance, and explores novel means for its prevention and treatment. The novel information will also be important for pharmaceutical companies to develop safer drugs to avoid antibody-drug-induced heart rhythm disorders.