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A multidisciplinary approach towards sustainable improvement in rare diseases care uniting Europe's top class vascular research to find new treatment strategies for vascular anomalies

Periodic Reporting for period 1 - V.A. Cure (A multidisciplinary approach towards sustainable improvement in rare diseases care uniting Europe's top class vascular research to find new treatment strategies for vascular anomalies)

Reporting period: 2019-03-01 to 2021-02-28

Approximately 7000 discovered rare diseases affect 10-15% of the world population and present significant medical burden with unmet medical needs. Vascular anomalies (VAs) are a group of rare diseases defined by blood- or lymph vessel dysfunction causing chronic pain, disabilities, and even sudden death. Effective therapeutic treatments for VAs are lacking and inherent challenge in the field is the scarcity of clinical knowledge and expertise due to limited number of patients affected per a specific rare disease. Therefore, VAs require life-long clinical management by multidisciplinary medical teams, including surgeons, interventional radiologists, geneticists etc and management is often partial, leaving patients with chronic pain, dysfunction, and lowered quality of life.

The European V.A. Cure network aims to address this unmet medical need by uncovering core mechanisms of disease initiation and maintenance and by leveraging this information for establishing novel therapeutic strategies for VAs. Project’s consortium assembled 7 world-leading academic institutions, 2 companies, and is supported by 9 partner organisations across Europe.

In V.A.Cure network 14 international early stage researchers are working with experts on reaching project’s objectives:

(1) identification of novel genes involved in VAs in patients,
(2) dissection of molecular mechanisms behind the diseases by in vitro modelling,
(3) in-depth analysis of tissular mechanisms in pathophysiological conditions through in vivo models, and
(4) pre-clinical testing of identified treatment strategies.
Thus far, researcher’s efforts led to discovery of new disease-causing genes, which are further investigated in animal models. Furthermore, the generation and analysis of extensive single-cell RNA sequencing data revealed fundamental insights how different subtypes of VAs arise.

To better understand and model the cellular and molecular mechanisms of specific VA-causing mutations, various cell lines from primary cells as well as iPS-derived endothelial cells (ECs) have been generated. Cutting-edge gene editing technologies were applied to induce point mutations, gene knock outs and knock ins, which allow high-resolution analyses of signaling pathways involved in VAs.

To tackle scientific questions from different angles and uncover molecular vulnerabilities of VAs, several new in vivo disease models were developed. Their application resulted not only in fundamental insights for understanding pathophysiological pathways but is also the foundation for the discovery and development of new therapeutic targets.
Our multidisciplinary research program is uniquely positioned to deliver novel therapeutic targets and molecules for the modulation of core signalling pathways we have recently found to be implicated in vascular anomalies. In addition, investigation of naturally occurring VA-causing mutations is a particularly powerful approach to unravel novel pathways that are crucial for normal vascular morphogenesis and function.

Thus, our network may also not only provide new therapeutic targets for relatively rare VAs, but also for cancer, diabetes and cardiovascular disease, in which dysfunctional vasculature is hallmark of disease progression.

V.A. Cure network aims to tackle important unmet scientific needs in the field of vascular diseases by identifying novel disease mechanisms and potential drug targets for vascular anomalies. V.A.Cure Network team covers the whole innovation chain- from patient to bench and back to the patient, project's experts hold overarching expertise in the three main signalling pathways involved in the development of the vasculature, and together they cover all relevant state-of-the-art technologies needed for the in-depth study of vascular anomalies.

The V.A. Cure project developed active collaboration between academia and industry and made significant progress in reaching all objectives. Thus far, V.A. Cure project contributed to development of ESRs careers in multiple ways:

1. High quality scientific basis- Through supervision and series of trainings & lectures given by project experts during two Network-wide meetings, ESRs are in a process of acquiring expertise in genetics, cell and animal models, imaging, technologies, and “omics” data analysis. All mentioned skills are highly sought-after in academia and the pharmaceutical industry.
2. Enhancing the transferable skills of the future -Since the start of the project, students learned to collaborate as a team, to engage in each other research topics and provide feedback, to present themselves and their research to different audiences, and to tackle complex ethical aspects in research. In addition, through their University PhD programs, ESRs have an opportunity to attend numerous workshops and courses in transferable skills.
3. Intensive non-academic exposure –ESRs are closely collaborating with project's companies though annual network meetings, bimonthly scientific meetings and secondments. Network developed close collaboration with partner organization in industry through trainings and workshops, booster meetings and secondment organization for ESRs.
4. Multi-employability- Students are in the process of obtaining skills in the field of vascular biology, research methods and state of the art techniques that are competitive in the job market. Students will be able to apply for the positions not only related to rare diseases and vascular anomalies, but also cancer, infectious and autoimmune diseases, retinopathies, and regenerative medicine research. Both sectors- academia and industry, have an interest in candidates with these qualifications.

V.A. Cure international team is on the way to provide more insight into the mechanisms of vascular diseases, provide realistic hope for patients, and give Europe a leading position in vascular anomalies research. In addition, highly complementary expertise in our multidisciplinary consortium significantly increases scientific impact of all groups and enables academic participants to stay at the forefront of vascular research with high clinical importance. Furthermore, through collaboration with project experts from academia, private sector will continue to resolve obstacles in product development, to strengthen R&D capacity, and gain insight into the markets and specific needs and requirements in this field of the research.

New genetic diagnostic tools will directly help society to achieve the goal of personalized medicine and precision therapy for rare diseases. Therapies we develop will bring relief to chronic and debilitating diseases in order to improve quality of life of patients. In addition to the scientific, human, and societal advances, there are economic incentives for health care system as the life-long clinical management of chronic disease can represent a significant economic burden.
Grafic representation of four project objectives
V.A.Cure Partner organizations
Academic and industrial Beneficiries of V.A.Cure project