Cardiac Manifestations in Myotonic Dystrophy Type 1: Arrhythmia Mechanisms and Novel Therapeutic Approaches
Abstract
Myotonic dystrophy is a form of muscular dystrophy and it is an inherited disease that affects the muscles and many other organs in the body. Specifically, weakness and wasting (shrinking) of voluntary muscles in the face, neck, lower arms, and legs are common in myotonic dystrophy type 1 (DM1). Muscles between the ribs and those of the diaphragm which moves up and down to allow inhalation and exhalation of air can also be weakened. DM1 is the most common form of muscular dystrophy found in adults. Currently, there is no cure or medication to control DM1 symptoms. DM1 is characterized by multiorgan impairments including the heart. Eighty percent (80%) of patients with DM1 have abnormal heart beats known as cardiac arrhythmias and can die suddenly. Cardiac arrhythmias and sudden cardiac death are major health concern as it is estimated that every day >1000 sudden cardiac deaths occur in the United States in general and in particular for DM1-affected individuals. Problems with heart rhythm and conduction will arise first and can cause shortness of breath, discomfort, palpitations, light-headedness, dizziness, loss of consciousness, and in severe cases, sudden cardiac death. The only available current treatment for more severely affected DM1 patients is the implantation of a pacemaker or a defibrillator. These are small devices that are placed in the chest or abdomen of most vulnerable patients. The main objective of this research is to better understand the causes of the electrical abnormalities (abnormal heart beat) seen in patients with DM1 and then device treatment option tailored to this disease. We will leverage our established expertise in the use of adult stem cells known as iPSCs derived directly from DM1 patients. These cells are transformed into heart cells in a dish and are patient-specific, which is a unique feature for individually targeted medicine. This way we are able to study, on case-by-case basis, the causes of abnormal heart beats and device appropriate therapies. In addition, we will use a mouse model of DM1 that was genetically engineered to carry the human mutations. This mouse shows DM1 phenotype similar to that seen in DM1 patients and will be used to correct the genetic defect and test new potential effective medications to reverse the heart electrical abnormalities seen in DM1 patients. Overall, the goal of this research is to identify the causes of heart electrical abnormalities in DM1 patients and come up with ways for interventions that will correct these abnormalities. We plan to achieve this by: 1) Studying the role of ion channels (these are pores through which ions such as sodium, calcium, and potassium enter cardiac cells) responsible for spreading the normal electrical activity throughout the heart and assess how they contribute to abnormal heart beat seen in DM1 patients. We will use state-of-the-art technology such as fluorescent probes applied to stem cells and DM1 mouse model that allows pinpointing to the site in the heart where the abnormal beat starts and follow how it spread throughout the heart. 2) Using sophisticated genetic tools known as molecular scissors, which can correct the genetic defect and therefore the disease expression in the heart. 3) Testing medications already approved by the Food and Drug Administration that can reverse the disease. The results of this research are expected to better understand the cardiac aspects in DM1 patients and thus be able to device new corrective therapies. The novel aspects of this proposed research are: 1) Finding out for the first time, what causes electrical abnormalities in the heart of DM1 patients. 2) The use of cells derived directly from DM1 patients combined with a mouse model that recapitulates the clinical characteristics of the disease. 3) The reversal of genetic mutations in heart cells from DM1 patients using DNA probes and genome editing tool biologics as well as in mouse model of DM1 as an animal model of p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110426
Entities
People
- Mohamed Chahine
Organizations
- Laval University
- United States Army