Cardiomyopathies associated with the DES gene mutations: molecular pathogenesis and gene therapy approaches

Abstract

Cardiomyopathy (CMP) is a common group of cardiovascular disorders. Genetic (primary) cardiomyopathies are related to abnormalities in more than 100 genes, including the DES gene encoding desmin protein. Desmin is an essential member of the intermediate filaments, ensuring the structural and functional integrity of myocytes. Mutations in the DES gene result in desmin-related cardiomyopathy with progressive course and poor prognosis. By now, specific therapy for cardiomyopathy has not been developed. Existing conservative and surgical treatment modalities target the rate of heart failure progression and sudden cardiac death prevention but have limited efficacy. The development of gene therapy and genome editing could allow for creating effective and specific methods of gene-based therapy for desminopathies. A number of studies have been published on the use of gene therapy for various genetic cardiomyopathies including those caused by the DES gene mutations, while genome editing has not been used yet. However, promising results have been obtained with CRISPR/Cas9 and TALEN editing systems to correct for “gain-of-function mutations” in some other genes, such as MYBPC3 and PLN. There is also evidence of the possibility to reduce the symptoms of desmin-related cardiomyopathy up to the normal function by knocking out the mutant DES allele, and preserved protein function provided by expression of the normal allele. We believe that genome editing approaches have an open perspective into the development of specific and effective methods to treat desminopathies.

Keywords

• cardiomyopathy
• desmin
• desminopathy
• medical genetics
• gene therapy
• genome editing
• crispr/cas9