Towards new therapies: can we beat genetic cardiomyopathies? – PhD defense Su Ji Han

Mutations are changes in DNA and occur naturally. Some of them arise spontaneously, while others are inherited from our parents. Most mutations have little or no effect on health, but some alter the function of genes and can contribute to inherited disorders or other diseases.

In the heart, inherited mutations can cause diseases that alter the structure and function of the heart muscle. These conditions may lead to dangerous heart rhythms, heart failure or even sudden cardiac death. Su Ji investigated these disorders, known as genetic cardiomyopathies.

The glue lost its function

Su Ji studied arrhythmogenic cardiomyopathy (ACM), a genetic cardiomyopathy that is often caused by mutations in proteins that act as the “glue” between neighboring heart muscle cells. These mutations weaken the connections between the cells, causing heart muscle tissue to be gradually replaced by fat and scar tissue.

To study ACM, Su Ji used stem cell-derived heart muscle cells and mouse models carrying a disease-causing mutation in plakophilin-2 (PKP2), the most commonly affected gene in ACM. With these methods, she discovered that the mutation reduced the amount of PKP2 and several other proteins that normally help keep heart muscle cells connected. Su Ji identified the molecular pathway responsible for this protein degradation and showed that blocking this process increased the levels of these important structural proteins again. This also improved the function of heart muscle cells carrying the PKP2 mutation, suggesting that this approach could form the basis for future therapies.

Low in energy

Surprisingly, these structural defects also affect how cells produce energy. Su Ji discovered that heart muscle cells lacking sufficient PKP2 protein struggle to increase energy production when energy demand rises. This is particularly interesting because for ACM patients, it is known that exercise can accelerate disease progression. She found that the problem lies in the mitochondria, the tiny structures inside cells that generate most of the cell’s energy and are often called the “powerhouses of the cell.”

Su Ji observed reduced expression of genes required for mitochondrial function in cells with reduced PKP2. This was linked to lower levels of PGC1α, an important regulator of cellular energy metabolism. Increasing PGC1α levels improved the expression of these genes and heart muscle cell function in cells with reduced PKP2. These findings suggest that impaired mitochondrial energy production is an important contributor to the development of ACM.

Editing out the mutation

Su Ji also investigated a mutation that causes hypertrophic cardiomyopathy (HCM) and is more prevalent in the Dutch population. HCM is typically caused by mutations in the sarcomere, a structure that is responsible for muscle contraction and characterized by thickening of the heart muscle. Using gene-editing technology, Su Ji tested different editing tools to directly target the mutation and was able to correct it in human stem cell-derived heart muscle cells. This restored their normal cellular function and forms a promising concept for future gene therapies for inherited heart diseases.

A highly rewarding journey

Su Ji looks back on her PhD as a challenging but highly rewarding journey. She liked the diversity it brought: “No two days were the same! This kept the work exciting and continuously pushed me to learn and grow,” Su Ji tells. She appreciated the international environment of the Hubrecht Institute and experienced contributing to projects with the potential to improve patients’ life as especially meaningful. A highlight of her PhD was getting her work accepted in a well-respected scientific journal.

A marathon, not a sprint

For Su Ji, one of the most challenging aspects of a PhD is dealing with uncertainty. “There is no guarantee that an experiment will work or that a project will lead to the expected results,” she tells. However, she recalls that these setbacks provided valuable lessons and helped her develop resilience and perspective to try different approaches.

According to Su Ji, a research environment where you feel supported is as important as the project itself. She advises people considering a PhD: “Remember that a PhD is a marathon, and not a sprint. Take care of your well-being, celebrate small successes along the way, and make sure to maintain interests and relationships outside of work as well.”