New approaches to common chronic diseases

What exactly causes the onset of type 2 diabetes? Could the patient’s own genes be activated to combat coronary artery disease? Top-level research not only finds answers to many questions relating to common chronic diseases, but also raises new ones. 

Cardiovascular and metabolic diseases constitutes one of the university’s strategic, top-level international research areas. The professors in charge of the research area are among the world’s leading scholars in their respective fields: Professor Markku Laakso in research addressing the genetics of type 2 diabetes and insulin resistance, and Academy Professor Seppo Ylä-Herttuala in research and development of gene therapy.

Genetic information changes the prevention and treatment of diabetes

What type 2 diabetes and cardiovascular diseases have in common is the fact that they are becoming increasingly widespread due to the prevalence of unhealthy lifestyle habits and the population’s ageing and weight gain. These diseases often go hand in hand, making each other worse: 75% of persons with diabetes die of cardiovascular diseases.

The onset of type 2 diabetes is affected by both lifestyle habits and risk genes, of which more than 90 have been identified. Laakso’s research group has been involved in the discovery of nearly all of them, shaping our understanding of the mechanisms of the disease. Previously, it was believed that increased insulin resistance in insulin sensitive tissues plays a key role in the development on type 2 diabetes, but it has turned out that the majority of risk genes actually reduce insulin secretion.

“This is also why many drug development programmes carried out within the pharmaceutical industry over the past years have focused on molecules that regulate insulin secretion,” Laakso explains.

As research data, Laakso's group uses the METabolic Syndrome in Men (METSIM) study comprising more than 10,000 men living in eastern Finland. The group has also been involved in the discovery of several gene variants relating to overweight, disturbed lipid metabolism, blood pressure and coronary artery disease.

At the moment, they are working on the sequencing of the entire genome of the METSIM data, seeking to discover new gene variants associated with early onset coronary artery disease. Recently, the group finished the METSIM study’s exome sequencing.  This method in which only exons, i.e. the protein-encoding regions of genes, are sequenced speeds up the discovery of gene variants associated with rare forms of diabetes.  In the RNA sequencing of the METSIM study’s adipose tissue samples, the group collaborates with Professor Jussi Pihlajamäki.

Furthermore, the investigators aim to identify new genetic and non-genetic biomarkers for type 2 diabetes, insulin resistance and coronary artery disease. The METSIM follow-up study led by Professor Johanna Kuusisto sheds light on the long-term complications of diabetes. A recently launched intervention study, on the other hand, compares the efficacy of a lifestyle intervention in the prevention of type 2 diabetes in genetically high and low risk individuals. The intervention is led by Associate Professor Ursula Schwab, and for their part, the findings enable increasingly personalised, genetically tailored prevention and treatment of diabetes. 

Gene therapy and epigenetherapy for cardiovascular diseases

“Cardiovascular diseases have been studied for a long time, yet we keep finding new approaches to their treatment,” Ylä-Herttuala says.

Developed by his group, gene therapy for severe coronary artery disease has already been tested in clinical trials led by Professor Juha Hartikainen at Kuopio University Hospital. The results are promising. Next, the plan is to carry out an extensive treatment trial within a European multi-centre study. This trial is based on so-called biological bypass, in which a growth factor gene is used to grow new blood vessels in the cardiac muscle.  The genetic preparation is packed into an adenovirus carrier and a special catheter is used to ensure that it gets injected precisely in the desired target.  The gene used in the treatment is a modified vascular growth factor gene, VEGF-D, now used for the first time in the treatment of humans.

“We are developing gene therapy further in order to obtain as natural and local effects as possible. Another new target for development is epigenetherapy, in which no genes are injected into the body; instead, the treatment is based on the activation of the patient’s own genes through epigenetic mechanisms,” Ylä-Herttuala says.

Ylä-Herttuala’s group was the first in the world to demonstrate that epigenetherapy can significantly reduce the size of myocardial infarction in an animal model. This can be achieved by injecting small RNA molecules into the regulatory area of the growth factor gene in cardiomyocytes. These RNA molecules activate gene encoding and thus increase the production of the growth factor and angiogenesis.

“The method is safe and could already become a treatment alternative in early coronary artery disease.”

The research consortium addressing cardiovascular diseases also includes the group of Professor Anna-Liisa Levonen, focusing on disease-related oxidative stress, and the group of Professor Pasi Tavi, focusing on the physiology of heart failure.

The Cardiovascular and metabolic diseases research area is engaged in extensive networks in Europe and the US, and the most significant funders include the National Institutes of Health in the US, the EU’s Framework Programmes, and the Academy of Finland. Ylä-Hettuala’s and Laakso's groups constitute part of the Finnish Centre of Excellence in Cardiovascular and Metabolic Disease, and they are in charge of the activities of the National Virus Vector Laboratory and the Genome Centre of Eastern Finland.