A new gene therapy approach to arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a complex, genetic cardiac disorder, leading to lethal arrhythmias and sudden cardiac death. The pathophysiology of ACM is closely linked to mutations in desmosomal genes, particularly the PKP2 gene, which encodes for the plakophilin-2 protein, a known desmosome stabilizer. Mutations in the PKP2 gene lead to reduced plakophilin-2 protein levels in cardiomyocytes, disrupting desmosome stability, altering cell synchronization, and resulting in the development of arrhythmias.

Current ACM treatment strategies, such as the use of antiarrhythmic drugs, primarily address the symptoms of the disease, not the underlying cause. Consequently, targeted and effective therapeutic interventions for this disease remain lacking.

Two recent studies, published in Nature Cardiovascular Research, have established the groundwork for developing gene therapy for arrhythmogenic cardiomyopathy. The proposed gene therapy strategy was to introduce a healthy PKP2 gene to restore plakophilin-2 levels in deficient cells. The authors demonstrated that adeno-associated virus (AAV)-mediated PKP2 restoration results in the re-formation of the desmosomal complex and consequently an improvement in contractile function. This was observed in three models mimicking the genetic and functional aspects of arrhythmogenic cardiomyopathy: PKP2c.2013delC/WT induced pluripotent stem (iPS) cell-derived cardiomyocytes (CMs), PKP2c.2013delC/WT engineered human myocardium (EHM), and Pkp2 mutant knock-in mice.

Importantly, PKP2 delivery restored not only cardiac PKP2 levels but also the levels of other junctional proteins, found to be decreased in response to the mutation. Using a high-throughput automated patch clamp platform, the SyncroPatch 384, the team lead by Eva van Rooij evaluated sodium currents in iPS-cell-derived CMs. They showed that the mutant PKP2 iPS-CMs demonstrated a significantly reduced sodium conduction, which was effectively restored to normal levels following treatment with AAV6–PKP2.

Of note, PKP2 overexpression in healthy cells did not induce any adverse effects, underscoring the treatment’s safety and specificity for ACM pathology.

Encouragingly, these findings are not just confined to the laboratory. In 2024, several U.S.-based clinical trials will explore this gene therapy’s potential in ACM patients with PKP2 mutations.

Overall, these studies suggest that PKP2 gene therapy holds promise for improving the clinical outcomes of arrhythmogenic cardiomyopathy patients and emphasize the potential of targeted gene therapy as a novel treatment avenue for heart disease.

Find the original articles here: Kyriakopoulou et al. and Bradford et al.

Learn more about the SyncroPatch 384, a revolutionary automated patch clamp system combining high quality electrophysiological data acquisition and analysis with state-of-the-art liquid handling: https://www.nanion.de/products/syncropatch-384/