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

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.

Disease of the desmosome

The mutations at the basis of ACM often occur in genes related to the desmosomes. These protein structures form the connections between adjacent heart muscle cells. Not only do they provide a structural link, but they also ensure that the heart muscle cells contract synchronously, allowing the heart to pump blood in a coordinated manner. The most frequently affected gene in ACM is PKP2, which encodes the plakophilin-2 protein, an essential part of the desmosomes. First author of the study Eirini Kyriakopoulou explains the effect of PKP2 mutations: “Patients with mutations in this gene often have lower levels of the plakophilin-2 protein in their heart muscle cells. The result is that the desmosomes, which are normally built up by meticulously binding all proteins together, now start to fall apart and are broken down by the cell. This weakens the connections between the heart muscle cells, which makes it difficult for them to work together in synchrony, leading to the development of arrhythmias.”

Gene therapy

With the molecular cause of ACM in mind, the researchers set out to develop a therapeutic approach that would target this cause and not just the symptoms. “For many patients with PKP2 mutations, the root of the problem is insufficient levels of plakophilin-2. Therefore, we explored the potential of gene therapy in ACM. We hypothesized that by introducing the healthy PKP2 gene into affected heart muscle cells, we might be able to restore plakophilin-2 levels to normal, thereby reinforcing the desmosomes and reducing the occurrence of arrhythmias in these patients,” says Kyriakopoulou.

Video showing engineered human heart muscle tissue in the lab. These ring-shaped structures have the ability to contract and can therefore be used as a model of the human heart to measure contractility. Credit: Eirini Kyriakopoulou. Video captured at the University Medical Center Goettingen.

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. “Three companies in the United States have announced that they will start clinical trials next year to test the therapeutic effect of this approach in patients, which is of course great news,” says Kyriakopoulou. The researchers at the Hubrecht Institute hypothesize that gene replacement therapy would be most useful in the early stages of the disease. Kyriakopoulou: “Once the disease has progressed so much that parts of the heart muscle have already been replaced by fat tissue, it is uncertain whether this approach would reverse already existing damage. Instead, we believe that it might be possible to prevent progression of early-stage disease to more severe stages.” Although the pre-clinical results and upcoming trials hold great promise, Kyriakopoulou emphasizes 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.”

Publication

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.