Interview with Tomáš Freiberger Ph.D., Lead Physician of the Genetic Laboratory of the Center for Cardiovascular and Transplantation Surgery (CKTCH) in Brno

1. Professor Freiberger, could you please briefly explain to our readers the activity which the genetic laboratory CKTCH in Brno does, in relation to HAE? 

I work in the genetic laboratory of the Center for Cardiovascular and Transplantation Surgery, where we deal with molecular-genetic diagnostics of primary immune disorders. This means that we look for mutations in the respective genes that are responsible for the development of these diseases. This also applies to hereditary angioedema. In patients with hereditary angioedema, we examine their genetic information, i.e. DNA, and look for some error in the genes that are responsible for the development of HAE. If we find it, it means confirmation of the diagnosis at the genetic level, and we can easily search among the relatives of these patients, if anyone else has the same genetic predisposition to develop this disease.

In addition to diagnosing hereditary angioedema, we are also involved in research. We are now conducting a large-scale study to find out which genetic factors influence the course of the disease. The causal mutation in the responsible gene is not the only factor, because it is known that even in patients who carry the same mutation – typically members of the same family – this disease can evolve very differently. Someone has a severe disease course, both in the number of attacks and their localization, someone, on the contrary, has a very mild course. This study is still ongoing, but I can reveal that so far we have not been able to find any significant genetic factor that would influence the severity of the disease. So I have no positive news in this regard. However, we found some changes in gene regulation. It appears that in patients, compared to individuals without HAE, some genes are regulated non-randomly and are more interrelated, but why this happens and what significance it has will be the subject of further research.

2. Has HAE scientific research brought any breakthroughs in recent years that you would like to inform our patient community about?

There has been quite significant progress in the field of genetics, both in the field of diagnosis and treatment. The history of hereditary angioedema is very long. Already in 1888, William Osler described this disease, observing episodic swelling in five successive generations. And then it took quite a long time to figure out what caused it. It wasn't until 1963 that Virginia Donaldson discovered that the cause was low levels of the protein C1 inhibitor in patients' blood. It took another 24 years, until 1987, before the gene responsible for this was discovered. And then again, it took some time to find other genes that also cause hereditary swelling. In the other diseases, however, the difference is that the level of the C1 inhibitor is normal, and the swelling is caused by other mechanisms, such as a defect in the gene for factor 12, which is also involved in blood clotting. Since 2006, when mutations in this gene were discovered, research has picked up speed. In the last five years, four or five more genes have been discovered whose defect is responsible for hereditary angioedema. However, most of these have only been detected in one family in the world, so some of these genes are still waiting to confirm their role in the development of the disease.

And another positive development in the field of genetics that I would like to mention is the development of treatment in the form of gene therapy, where it is possible to inject the corrected gene using a viral vector, a viral carrier, into the patient's cells, ideally into the liver cells, where the synthesis, the formation of the corrected C1 inhibitor takes place. This is already in the clinical trial phase, and if it works, it could solve the problem of HAE patients in the long term perspective. And it is not the only option of gene therapy, another way has emerged where there is so-called gene editing. In this case, it is a targeted removal of the gene that is responsible for the formation of the molecule of kallikrein, a molecule that is involved in the formation of edema in patients with hereditary angioedema. The first phases of clinical testing are already underway.

3. How do you assess the current development of new drugs (including genetic drugs) for the treatment of HAE? Where do you see the biggest shift and where, on the contrary, are there still reserves and there is a lot of catching up to do? 

From a research and expertise point of view, I am very optimistic. The progress is really noticeable, in the field of hereditary angioedema a lot of positive developments have happened in the last ten years. New drugs or dosage forms are emerging, this refers to oral administration, and we are also witnessing the first possibilities of HAE gene therapy.

 Currently, a number of clinical trials of new drugs are underway, but it is important to realize that the development of new drugs is always a long run. I am not an expert in this area, so I cannot estimate the time horizon when these drugs will be available to patients, but once the drug has reached the clinical trial stage, and unless there is a problem with the safety or efficacy of the drug, the steps and procedures are clear. It is about including a sufficient number of patients willing to participate in clinical trials so that valid information is obtained and the drug can be put into practice. Soon, we can expect the arrival of new drugs on the market.

Perhaps I see reserves in the fact that modern treatment is still very expensive and therefore less accessible. As I mentioned, the development of new drugs is complicated and very expensive, and this is reflected in their price and availability. If we could intervene in some way to make these medicines more accessible, that would certainly be a good thing, and I think that is also one of the roles of patient organisations to influence politicians to push for the availability of new medicines.

4. What kind of assistance does your team offer to families of patients diagnosed with HAE? For example, in the field of counselling on genetic testing, family planning, etc.? 

I am actually the head of our genetic laboratory, where we mainly perform genetic diagnostics. We usually receive samples that are taken from patients in their doctors' offices, whether immunologists or geneticists. Recently, the insurance company requires that the indication of genetic testing be performed by a clinical geneticist. Therefore, we do not come into contact with patients, but I personally work once a week in the outpatient clinic of clinical genetics, where I provide genetic counselling, both in terms of indication and interpretation of genetic test results, as well as determining the risk to offspring in family planning, prenatal diagnostics, preimplantation diagnostics, i.e. diagnosis before conception, and other related issues.

5. What advice would you give patients and their relatives for a better start in life for their children?

I would definitely advise them to listen to their doctors, to follow their advice and instructions, not to be afraid to ask them about the possibilities that current medicine offers, to know about new drugs, to know about the possibilities of genetic diagnosis and genetic counselling. To behave responsibly, to have their children diagnosed in time so that they and the children receive the necessary treatment in time.

Tomáš Freiberger works as a professor of immunology at the Faculty of Medicine of Masaryk University and as the head physician of the genetic laboratory of the Center for Cardiovascular and Transplantation Surgery (CKTCH) in Brno. Professor Freiberger is a member of the Czech Society of Allergology and Clinical Immunology (CSAKI) and the European Society for Immunodeficiencies (ESID). He also contributes to several scientific journals in the fields of genetics and immunology.