June 19, 2024

Scientific Breakthrough: Groundbreaking Gene Therapy for Genetic Heart Disease Shows Promise in Preclinical Trials

A team of researchers at the Hubrecht Institute has made significant progress in developing a gene therapy for arrhythmogenic cardiomyopathy (ACM), a genetic heart disease that affects 1 in every 2,000 to 5,000 individuals worldwide. This groundbreaking approach, which focuses on replacing the PKP2 gene, has shown remarkable structural and functional improvements in laboratory models of the disease.

The study, led by Eva van Rooij, was recently published in Nature Cardiovascular Research. The findings have paved the way for multiple clinical trials set to begin in the United States in 2024. These trials aim to assess the clinical potential of this gene therapy approach in ACM patients with PKP2 mutations.

ACM is a progressive heart disease characterized by arrhythmias and the potential for sudden cardiac arrest. Current treatment options mainly address the symptoms and do not target the underlying cause of the disease. Patients typically receive antiarrhythmic medications and implanted cardioverter-defibrillators (ICDs).

Over time, ACM leads to the replacement of heart muscle with fat tissue, resulting in deteriorating heart function and, in severe cases, heart failure. Heart transplantation is often the last resort, but the limited availability of suitable donor organs poses a significant challenge. Therefore, finding effective treatments that address the cause of ACM is crucial.

Researchers have found that mutations in genes related to desmosomes, the protein structures that connect adjacent heart muscle cells, form the basis of ACM. The most commonly affected gene is PKP2, which encodes the plakophilin-2 protein, a vital component of desmosomes. Mutations in PKP2 lead to lower levels of plakophilin-2 in heart muscle cells, causing the desmosomes to weaken and fail, resulting in arrhythmias.

In light of these molecular insights, the researchers developed a gene therapy approach targeting the root cause of ACM. By introducing a healthy PKP2 gene into affected heart muscle cells, they aimed to restore plakophilin-2 levels, strengthen the desmosomes, and reduce the occurrence of arrhythmias.

Preclinical models of ACM substantiated the feasibility and effectiveness of this approach. In human heart muscle cells grown from stem cells, the delivery of the healthy PKP2 gene restored plakophilin-2 levels and improved sodium conduction, crucial for effective contraction. These promising results were further confirmed in engineered human heart muscles, demonstrating improved contractility after receiving the healthy PKP2 gene.

To test this strategy in vivo, the researchers performed PKP2 gene replacement in a mouse model of ACM. The results were remarkable, with the recovery of desmosomes and heart function.

Following these groundbreaking findings, three companies in the United States are planning to initiate clinical trials in ACM patients with PKP2 mutations next year. While the research team is enthusiastic about the potential therapeutic effect of this gene therapy approach, they caution that it may be most effective in the early stages of the disease.

Eirini Kyriakopoulou, the first author of the study, emphasizes that once parts of the heart muscle have already been replaced by fat tissue, it remains uncertain whether this approach can reverse existing damage. Therefore, the researchers believe that the gene therapy might be most effective in preventing the progression of early-stage disease to more severe stages.

However, despite the promising results and upcoming clinical trials, the commercial availability of this gene therapy treatment may still be years away. Confirming its efficacy in patients and addressing any safety concerns will be critical steps before considering widespread clinical application.

Nevertheless, the work conducted by the researchers at the Hubrecht Institute has laid a solid foundation and offers hope for the development of an effective treatment for ACM.