Individualized Medicine for Cardiomyopathies

Idiopathic dilated cardiomyopathy is a heritable, progressive disorder that ultimately leads to heart failure. The development of effective therapy is significantly hindered by the heterogeneous nature of dilated cardiomyopathy. This manifests as both locus heterogeneity (mutations in different genes) and phenotypic variation (people with the same causative mutation exhibit highly variable phenotypes).

While causative mutations have been identified in more than 50 genes, these genes account for less than half of heritable dilated cardiomyopathy cases. Even less is known about genetic modifiers that are presumably responsible for phenotypic variation. Therefore, discovering additional causative and modifier genes is critical for the development of individualized medicine for dilated cardiomyopathy.

The Zebrafish Genetics Laboratory has generated several cardiomyopathies among the first adult zebrafish models, including:

• Acquired models for cardiomyopathies induced by doxorubicin.
• Inherited models for cardiomyopathies induced by genetic mutations in titin, BAG3 and MYH7.

Using a transposon-based insertional mutagenesis screening platform, we demonstrated the feasibility of discovering genetic modifiers of cardiomyopathy via screening a zebrafish insertional cardiac mutant collection. Using an MMEJ-based genome editing technology, we established another genetic platform to discover genetic modifiers of cardiomyopathy via knocking down genes in F0 animals. While deleterious modifiers such as DNAJB6 and SORBS2 suggest new cardiomyopathy genetic factors, salutary modifiers such as mTOR and RXRAA prompt novel therapeutic target genes.

Using these powerful genetic tools, we are searching for new genetic modifiers and developing new therapeutic strategies. We also are assessing these therapeutic strategies in zebrafish models for cardiomyopathies of different etiology, aiming to accelerate the implementation of individualized medicine for human cardiomyopathies.