Grant: Project Grant

Myotonic Dystrophy Type 1 (DM1) is the most common form of adult muscular dystrophy affecting as many as 1 in 500 people in some regions of Quebec. DM1 can manifest in infancy, in old age or at any stage in between affecting all systems in the body including eyes, heart, brain and muscle (myotonia). Infants with DM1 often do not survive due to weak lungs and insufficient breathing; those who survive are usually affected by intellectual delay. Cells from DM1 patients when studied under the microscope reveal bright spots known as RNA foci. These foci are products of the mutated DM1 gene; in addition to helping make the diagnosis of the DM1, it is believed that these bodies interfere with normal cell function and are thus involved in causing the disease itself; the foci are in this sense a therapeutic target. When these aggregates are broken apart, proper cellular function is often restored, making "foci busters" good candidates for DM1 therapy. We shall therefore treat DM1 patient cells with thousands of compounds, including hundreds of currently used FDA-approved medications and using automated microscopy looking for reduction of these aggregates. Similarly we will interfere with 1000's of genes in the body and look for similar impact. Importantly we will use muscle cells from DM1 patient to do this test. Drugs and genes which reduce the number and or size of aggregates will be next tested in a mouse genetically engineered to have DM1 which display signs similar to that seen in humans. We will compare untreated and drug-treated mice to determine if the medications improved their DM1 signs. If treated animals show improved signs; this information could be used as the basis for a clinical trial. Using medications which are already in use for other conditions is advantageous as it by-passes the significant time required for safety and efficacy testing of newly developed drugs, saving both time and money.