Researchers at the Hubrecht Institute have made significant progress in developing a gene therapy for arrhythmogenic cardiomyopathy (ACM), a genetic heart disease that affects 1 in 2,000 to 1 in 5,000 people worldwide. The study, led by Eva van Rooij and published in Nature Cardiovascular Research, focuses on replacing the PKP2 gene frequently affected in ACM patients.

Arrhythmias characterize ACM and can lead to sudden cardiac arrest. Current treatments for the disease only address the symptoms and do not target the root cause. This new gene therapy approach aims to restore the levels of the plakophilin-2 protein (encoded by the PKP2 gene) in heart muscle cells, reinforcing the connections between cells and reducing the occurrence of arrhythmias.

The researchers demonstrated the feasibility and efficacy of the gene therapy in laboratory models of ACM. They successfully restored plakophilin-2 levels in human heart muscle cells grown from stem cells, improving their sodium conduction and contractility. The therapy also showed positive results in engineered human heart muscles and a mouse model of ACM, leading to the recovery of desmosomes (protein structures that connect heart muscle cells) and improved heart function.

Based on these promising laboratory results, multiple clinical trials will begin in the United States in 2024 to explore the potential of this gene therapy approach in ACM patients with PKP2 mutations. However, it is essential to note that the availability of this therapy for commercial use may still take several years, as further testing and addressing safety concerns are necessary.

The researchers believe this gene therapy approach may be most effective in the early stages of ACM before significant damage to the heart muscle has occurred. It can potentially prevent the disease’s progression to more severe stages. However, it is uncertain whether the therapy can reverse existing damage in advanced cases.

While this gene therapy offers hope for ACM patients, confirming its efficacy and addressing safety concerns is essential before it can be widely used. Nevertheless, this study provides a solid foundation for further research and clinical exploration of PKP2 gene therapy as a potential treatment for ACM.

References

• Hubrecht Institute. (2023, December 7). Research lays groundwork for promising new gene therapy approach for genetic heart disease: Clinical trials imminent. MedicalXpress; Hubrecht Institute. https://medicalxpress.com/news/2023-12-lays-groundwork-gene-therapy-approach.html
• Kyriakopoulou, E., Versteeg, D., de Ruiter, H., Perini, I., Seibertz, F., Döring, Y., Zentilin, L., Tsui, H., van Kampen, S. J., Tiburcy, M., Meyer, T., Voigt, N., Tintelen, van J. P., Zimmermann, W. H., Giacca, M., & van Rooij, E. (2023). Therapeutic efficacy of AAV-mediated restoration of PKP2 in arrhythmogenic cardiomyopathy. Nature Cardiovascular Research, 1–15. https://doi.org/10.1038/s44161-023-00378-9