Geneticist Miikka Vikkula on how studying genetic causes of ‘rare diseases’ such as vascular anomalies leads the way to precision medicine.
Most ‘rare diseases’ have a clear genetic cause. This is commonly a mutation in a single gene responsible for the symptoms in most patients with a specific disease. With the development of high-throughput technologies, the identification of such mutations has become easier. This greatly enhances the understanding of the disease and also makes possible a quicker and more accurate diagnosis. For many ‘rare diseases’, the underlying genetic backbone is still unknown, mainly because the research resources are scarce and the sorts of diseases plenty. Yet, 30 million EU citizens are estimated to be affected.
Towards precision medicine
Studying the genetics of rare diseases not only benefits the affected patients. Due to the clear relation between the genetic mutations and cellular dysfunctions, this research gives precious insights into pathological pathways, which are often also involved in other diseases. For example, mutations in the so-called PIK3CA gene were found to be responsible for several rare diseases, including vascular malformations, but they also play a key role in various cancers, including colon and ovarian cancer. Research into rare diseases is therefore a promising route towards precision medicine.
Based at the de Duve Institute, UCLouvain in Brussels, Belgium, the human genetics research group of Professor Miikka Vikkula tries to unravel the genetic bases of such diseases. A few months ago, Vikkula received the Generet Prize, a prestigious Belgian prize for research on rare diseases, for his work on vascular anomalies. These localised lesions consist of malformed blood or lymphatic vessels, which can be found anywhere in the body – from skin to various organs. The lesions may be innocent, like ‘port-wine stains’. However, the rare, severe forms cause chronic pain, skin ulceration, bleeding, muscle weakness and other dysfunctions, and seriously diminish the patient’s quality of life.
In collaboration with the Center for Vascular Anomalies at the neighbouring University Hospital Saint-Luc, Vikkula’s group has found a new treatment for a specific vascular anomaly, venous malformation. They discovered that people with this disease have a mutation that makes vascular cells over-activate a specific signalling cascade involving the mTOR protein. Rapamycin (also known as Sirolimus), an existing drug that is used against graft rejection, inhibits this pathway, and the groups decided to investigate the effects of the drug on venous malformations.
Before going to human trials, they generated a mouse model, on which rapamycin stopped lesion development. Thereafter, they were able to show in two small groups of patients (phase 2A and 2B studies) that Rapamycin drastically relieved patients from their painful symptoms. One of them, who suffered from chronic headaches, is now working full-time again. A large phase three trial, ‘VASE’ (Vascular Anomaly-Sirolimus-Europe) is now being run.
The research began a long time ago with genetic analyses on a large family with multiple individuals with a venous malformation. In 1996, the Vikkula lab found the inherited mutation that caused the malformation of the veins. However, this did not explain why most veins in the affected family members were normal, and only localised lesions formed. It took the geneticists more than ten years to find the explanation, when they discovered a second mutation in the cells of the malformations themselves.
Only cells with both mutations develop the disease. The second mutation is a somatic mutation, which means that it is, in contrast to the one discovered first, not present in the inherited DNA, but only in the DNA of the cells in the affected tissue. It could therefore only be detected in tissue biopsies and not in the commonly-analysed blood samples. Moreover, as the biopsies contain little material, the detection was enabled by the increased sensitivity of modern ‘next generation sequencers’ (NGS).
Bench to bedside
Once the genetics and cellular mechanism of the disease were discovered, the next challenge was to bring this knowledge to clinical use. Here, this route was relatively short owing to several parameters. The most important one was the possibility to use an existing drug for another purpose (repurposing). As the safety of this drug was already tested in clinical trials, it was quickly approved for trials in vascular anomaly patients.
The development shows how a better understanding of the disease due to genetic research leads to a more precise and effective treatment. Until now, the only available treatments for vascular anomalies – laser-therapy, sclerotherapy and surgery – aimed to destroy or remove the abnormal vessels, generating a scar. These treatments are often ineffective or even impossible due to the size and localisation of the lesions, and regrowth may occur after partial treatments. The novel treatment tackles the disease at its origin by inhibiting the formation of the lesions. It gives patients a higher quality of life while reducing the burden of their treatments.
Next to vascular anomalies, the Vikkula lab studies a variety of developmental disorders of the cardiovascular and skeletal systems, as well as certain cancers. One of the current projects, financed by WELBIO, focuses on primary lymphedema. Patient samples are the indispensable starting point for this research. Together with the Center for Vascular Anomalies, 20 years ago the Vikkula lab started to collect samples of patients with rare vascular anomalies. This unique biobank today contains thousands of samples and associated data on the patients’ disease history. It has been the bases of multiple discoveries in the past and is an invaluable mine for future research.
Another essential asset of the lab is ‘Highlander’, an in-house developed software. It is used to analyse the enormous amounts of data that today’s next generation sequencing techniques generate. The software is coupled to a database with variant data and gene annotations from the lab and from outside sources. Highlander uses this database and advanced filtering tools to distinguish the true mutations from the considerable numbers of false positives. It thus helps the researchers to identify the changes-of-interest amongst tens of thousands of variants.
Together with Professor Boon at the Center for Vascular Anomalies, Vikkula has initiated VASCAPA, a patient association that supports people and parents of children with vascular anomalies. Together, they also head the Working Group on Vascular Anomalies (VASCA) at the European Reference Network (ERN) on Rare Vascular Diseases (VASCERN), which unites over 30 European clinical centres specialised in these diseases. In addition, the Vikkula lab co-ordinates the European Training Network (ETN) V.A. Cure, which will train young scientists in vascular research at multiple institutions across Europe. The genetics research of the Vikkula lab has thus become a hub of collaborative, multidisciplinary research, linking patients and clinics on the one site to bioinformatics, statistics, mathematics, artificial intelligence and developmental biology on the other.
Since the laborious discovery of the first second-hit somatic mutation, the Vikkula lab also found – now knowing where to search – somatic mutations that alone explain the occurrence of vascular anomalies without familial inheritance. This has opened the doors for various groups around the world to look for the same in various so-called ‘sporadically occurring diseases’. The Vikkula lab also continues its search, as they think that more vascular anomalies as well as other diseases are caused by somatic mutations.
Meanwhile, the group also discovered two ‘novel’ inherited vascular diseases, that is, diseases that were not recognised before. In these diseases (called CM-AVM), inherited genetic mutations can drive the formation of vascular anomalies anywhere in the body, even inside the brain; they are potentially deadly. These discoveries were again based on a tight collaboration between genetic and clinical research.
The genetic research field has been revolutionised by technological developments in DNA sequencing, which have made analyses faster, cheaper and more sensitive. While researchers fully exploit these advancements, the increasing regulations on data sharing hinder the work. Collaboration and sharing are the key to success in the field of ‘rare diseases’.
As the genetic cause of many such diseases are yet to be identified, more funding for basic research is badly needed. We also need to develop novel bioinformatic analysis methods for exploring human genome data. In combination with generation of animal models, and the repurposing of existing drugs, rapid changes in patient management can be achieved. This gives great hope for the numerous individuals suffering from a rare disease today.
Professor Miikka Vikkula
Laboratory of Human Molecular Genetics (GEHU)
Université catholique de
+32 2 764 7490