Cardiomiopatías de origen genético

Our research into cardiovascular disease is based on a simple principle: create to understand, create to treat.

Animal models are essential investigative tools for expanding our understanding of disease; however, the generation and maintenance of genetically modified mouse colonies for research is costly. We have developed an alternative method that uses adeno-associated virus (AAV) vectors, widely used for gene-therapy approaches, to express disease-causing dominant-negative mutants to generate disease models in wild-type mice. Single systemic injection of AAV virus is more versatile, cost-effective, simpler, and time-efficient than transgenic approaches for generating mutant animals.

Our major area of interest is arrhythmogenic cardiomyopathy (ACM). This heart muscle disease is characterized by right ventricular anatomical abnormalities and ventricular arrhythmias that can lead to sudden cardiac death, especially in young athletes. To be able to study the effect of exercise on hearts of mice carrying the most prevalent ACM-associated mutation in plakophilin-2 (PKP2), we used AAV to express the R735X mutant in wild-type mice. Our work shows that injected AAV-R735X animals develop an overt ACM phenotype when subjected to endurance training, supporting the recommendation for exercise cessation recommendation in carriers of this mutation.

Recent studies of our group have also discovered a connection between the new SARS-CoV-2 virus and PKP2 in heart desmosome homeostasis, which generates a transient ACM phenotype in patients with cardiac infection, identifying new targets for COVID-19 treatments.