Thesis Defense Joep Eding: RNA Targets in Cardiac Disease

Cardiac disease
Cardiovascular disease (CVD) is the leading cause of death worldwide. Myocardial infarction, known also as a heart attack, is a relevant contributor to CVD-related deaths. While a heart attack by itself is often not lethal, it causes significant damage to the heart tissue – on average, one billion cardiac muscle cells are lost during one such event, and the body is unable to naturally replenish this loss afterwards. This makes the heart progressively weaker and eventually leads to death due to heart failure. Treatment options after a myocardial infarction are focused on damage control, and are so far not able to actually repair the heart and fully cure the patient. Therefore, new therapies that are able to repair the heart after myocardial infarction are being sought. One such approach is RNA therapeutics.

RNA therapeutics
RNA therapeutics aim to modulate RNA levels in the cells. Some types of RNA enable the production of proteins inside our cells, based on information they receive from DNA. Other types of RNA are able to regulate this production, for example by speeding up or slowing down the rate at which RNA helps produce proteins. One such regulating RNA is known as microRNA (miR). MiRs also play an important role in different diseases, among them cardiac disease. In order to understand and control these illnesses, scientists can target and disable miRs by constructing small molecules known as antimiRs. In his PhD, Eding showed that antimiRs function differently in healthy rats compared to rats that had cardiac disease. This may be important for examining how RNA treatments would work when treating cardiac disease patients.

Challenges in targeting the heart
One subgroup of microRNAs, the miR-15 family, regulates heart muscle cell multiplication, and disabling them with antimiRs protects the heart after myocardial infarction in mice. However, making sure the antimiRs actually arrive to the heart remains a big challenge. Drugs often get washed out of the heart tissue very quickly, which may also cause them to produce unwanted reactions in other areas of the body. Eding and his colleagues have tested delivering antimiRs inside a hydrogel solution, to see whether hydrogel helps to deliver the drug to the heart more efficiently. They saw that this method of delivery increased the effect of the drug. By conducting further experiments on larger animals, researchers will be able to see whether this method could be applied to human patients in the future.

Cardiac disease on a single-cell level
With the advent of single cell RNA-sequencing techniques, which allow us to measure the activity of genes in individual cells, researchers are now able to investigate how different diseases affect gene activity in a single cell. Doing so enables researchers to take a much better look at the specific molecular mechanisms of diseases. During his PhD, Eding has used this technique to study hypertrophic cardiomyopathy,  a common genetic cardiac disorder. As a result, he and his colleagues gathered a wealth of new molecular insights into this condition. Among other findings, they identified genes that are correlated to cardiac muscle cell size. This group of genes presents a valuable set of potential new targets for improving heart function through RNA based approaches.