Microscopy image showing heart muscle cells (gray) in a mouse heart. The plakophilin-2 protein (green) is present in the desmosomes connecting adjacent heart muscle cells. After introduction of the healthy PKP2 gene, extra plakophilin-2 (red) is present in the cells (visible as yellow in places where green and red overlap). This localizes to the desmosomes, leading to their structural recovery. Credit: Eirini Kyriakopoulou. Copyright: Hubrecht Institute.

Promising new gene therapy approach for genetic heart disease: clinical trials imminent

7 December 2023: Published in Nature Cardiovascular Research, researchers from the Giacca Group have collaborated to lay the foundation for the development of a gene therapy for the genetic heart disease arryhthmogenic cardiomyopathy (ACM).

Researchers from the Giacca Group, ICGEB, and King’s College London, in collaboration with the Van Rooij Group, Hubrecht Institute and UMC Utrecht, have published findings of their most recent collaboration where their approach, based on replacement of the PKP2 gene, led to significant structural and functional improvements in laboratory models of the disease. The study, realized with support of the Dutch Heart Foundation, was published on 7 December 2023 in Nature Cardiovascular Research. Multiple clinical trials will start in 2024 in the United States to explore the clinical potential of this approach in ACM patients with PKP2 mutations.

Arrhythmogenic cardiomyopathy (ACM) is a genetic heart disease that affects 1 in 2,000 to 1 in 5,000 people worldwide. It is characterized by arrhythmias and can lead to sudden cardiac arrest. Current treatment of the disease usually consists of antiarrhythmic drugs and implantable cardioverter-defibrillators (ICDs), which are focused solely on treating the symptoms rather than targeting the root of the problem. The disease is progressive, with an increasing part of the heart muscle being replaced by fat tissue and heart function deteriorating over time. This can eventually lead to heart failure. In severe cases, a heart transplantation can be performed as a last resort, but this is complicated by long waiting lists as a result of the limited availability of suitable donor hearts. There is therefore an urgent need for effective treatments that target the cause of ACM.

From the lab to the clinic

Following the promising laboratory results, the next step is to investigate the clinical potential of this gene therapy approach in ACM patients with PKP2 mutations. While the pre-clinical results and upcoming trials hold great promise, first author, Eirini Kyriakopoulou emphasises that the commercial availability of this approach could still take several years. “Apart from the evident need to confirm its efficacy in patients, it is also crucial to address and eliminate any safety concerns before considering its clinical application. Nevertheless, our work provides an important basis to build on.”


Therapeutic efficacy of AAV-mediated restoration of PKP2 in arrhythmogenic cardiomyopathy. Eirini Kyriakopoulou, Danielle Versteeg, Hesther de Ruiter, Ilaria Perini, Fitzwilliam Seibertz, Yannic Döring, Lorena Zentilin, Hoyee Tsui, Sebastiaan J. van Kampen, Malte Tiburcy, Tim Meyer, Niels Voigt, J. Peter van Tintelen, Wolfram H. Zimmermann, Mauro Giacca and Eva van Rooij. Nature Cardiovascular Research, 2023.