Researchers Identify New Mechanism of Disease in Familial DCM

Researchers at EMBL Heidelberg have made significant progress in understanding the molecular underpinnings of a particular form of familial DCM and tested gene-editing approaches for treating such disorders.

Scientific illustration alluding to the role of gene and genome editing strategies in studying heart disease. The Steinmetz group found that gene editing can help correct mutations causing dilated cardiomyopathy and a genome-wide screen can be used to understand the molecular consequences of such mutations. Credit: Joana Gomes Campos de Carvalho/EMBL

In the first study, the team showed that a mutation in the RBM20 gene can cause the RBM20 protein to localize to the cytoplasm of the cell instead of the nucleus where it is normally found. This mislocalization of RBM20 can worsen disease phenotype, similar to other diseases involving protein mislocalization.

The team then used a genome-wide CRISPR-Cas9 screen and image-enabled cell sorting (ICS) to identify a protein—TNPO3—as being responsible for transporting RBM20 from the cytoplasm to the nucleus. They also found that mutations in RBM20 can prevent this interaction, resulting in RBM20 accumulating in the cytoplasm.

In the second study, the researchers used a next-generation CRISPR-based system called base editing to selectively reverse mutations in RBM20 in cardiomyocytes. They injected mice carrying Rbm20 mutations with a specially created viral vector that selectively targets cardiomyocytes and that carries a gene-delivery system that allows the genetic code of these cells to be edited at the site of the mutation.

Within three months of this treatment, the researchers saw improvement in several disease phenotypes, such as heart pumping function, splicing deficiency, and expression of heart failure biomarkers. They estimate that they could reverse the mutation in almost 70% of the cardiomyocytes in the recipient mice, an impressive figure for therapies of this kind.

The researchers believe that these findings could lead to new therapeutic approaches for DCM patients, and could also have potential as a preventative measure for those at very early stages of the disease or those who carry similar genetic mutations but have not yet developed DCM.

Julia Kornienko et al, Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3, Nature Communications (2023). DOI: 10.1038/s41467-023-39965-6

Markus Grosch et al, Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy, Nature Communications (2023). DOI: 10.1038/s41467-023-39352-1