Reference networks and research for rare diseases

Reference networks and research for rare diseases
© iStock/scanrail

Health Europa looks at the diagnosis and treatment of rare diseases and related research efforts. Focusing on the European Reference Networks and the New Modalities ecosystem in Finland.

Rare diseases are those that affect no more than five in 10,000 people. According to the European Commission, when taken together, between 5,000 and 8,000 rare diseases affect the daily lives of around 30 million people in the EU – many of whom are children. Rare and complex diseases can cause chronic health problems and many of them are life-threatening.

Examples of rare diseases include:

  • Cystic fibrosis, a hereditary disease that damages the lungs, digestive system and other organs, affects around one in every 9,000 Europeans
  • Hepatoblastoma is a very rare paediatric liver tumour mainly affecting very young children (0-3 years). EU incidence is only one in five million
  • Fibrodysplasia ossificans progressiva, which affects only 3,500 people worldwide, causes bone to be formed in muscles, tendons, ligaments and other connective tissue.

In a publication entitled ‘European Reference Networks: working for patients with rare, low-prevalence and complex diseases’, the European Commission explained that in the field of oncology alone, for example, there are ‘almost 300 different types of rare cancers and each year more than half a million people in Europe are diagnosed with one of them. Many of those affected by a rare or complex condition do not have access to diagnosis and high-quality treatment. Expertise and specialist knowledge may be scarce because patient numbers are low.’


To help tackle the challenges posed by rare diseases in Europe, European Reference Networks (ERNs) – virtual networks involving healthcare providers across Europe – have been established. They aim to facilitate discussion on complex or rare diseases and conditions that require highly specialised treatment, and concentrated knowledge and resources.

According to the Commission, health systems in the European Union aim to provide high-quality, cost-effective care. This is particularly difficult, however, in cases of rare or low-prevalence complex diseases which affect the daily lives of around 30 million EU citizens, and so ERNs help here.

Interviewed in the ‘European Reference Networks’ publication, the European Commissioner for Health and Food Safety, Vytenis Andriukaitis, said: ‘With ERNs, patients with rare and complex conditions will be able to benefit from the best treatment and advice available in the EU for their specific condition. Their doctors will have access to a highly specialised pool of colleagues from all over Europe.

‘In the first phase, over 900 healthcare units from nearly all EU Member States will work together in 24 thematic networks. They will cover a wide range of conditions, from bone disorders to blood diseases, from childhood cancer to immunodeficiency. They will facilitate access to diagnosis, treatment and provision of affordable, high-quality and cost-effective healthcare.’

Andriukaitis also discussed the ERNs during his speech at a rare disease event in the European Parliament, Brussels, in February this year as a part of Rare Diseases Day 2018, which also saw the ERNs celebrate their first anniversary. Here, he said: “I am a great believer in – and supporter of – the European Reference Networks for rare, low prevalence and complex diseases.”

He went on: “Exactly one year ago I was at Leuven University Hospital with the Belgian Minister of Health – Madam De Block – to launch the European Reference Networks. Today I am with you to celebrate one year of success of the 24 ERNs that are now operating across Europe.

“I am extremely grateful for the continuous work that you are doing for patients, alongside healthcare professionals, researchers, policy makers and hospital managers – working together to improve the quality of life of millions of people in Europe suffering from a rare disease.”

The Commissioner then discussed some of the progress which has been made since the adoption of the Cross-Border Healthcare Directive in 2011, focusing on:

  • The creation of a legal framework for the ERNs
  • The launch of the first call and the ERN board of Member States approving the 24 networks
  • The fact that the ERNs are now operational and the first patients are now directly benefitting from this innovative European co-operation.

“Of course, we still have a long way to go – but we have certainly made a most promising start!” he said.

Going on to highlight what has been achieved in the area of clinical care, Andriukaitis said: “The networks’ key IT tool – the Clinical Patient Management System – was launched on 20 November 2017, and by now already 67 consultation panels have been opened.

“On knowledge generation and knowledge sharing, by gathering a pool of patient data, ERNs are already very well placed to facilitate large clinical studies to improve the understanding of diseases and support the development of new medicinal products. Now that the framework is in place and the ERNs are up and running, we need to focus on how to maximise their effectiveness and ensure their sustainability.”

Nevertheless, challenges remain, and the Health Commissioner told his audience of what he saw as three immediate issues: “The first and most important challenge,” he said, “is to ensure the integration of ERNs into national or regional healthcare systems.”

This includes:

  • Assessing changes required in the legal framework of each member state to properly integrate ERNs into their healthcare systems
  • Deciding on the pathway and mechanism for referring patients to an ERN
  • Defining how Member States support the ERNs.

“I can assure you that the Commission is very active at technical, strategic and political level to help national authorities speed up the process of integration,” the Commissioner added.

For Andriukaitis, the second challenge is to ensure full support to the ERNs. Here, he explained: “Hospital managers are key players in the success of the ERNs, many of whom already fully appreciate the benefits that ERNs will bring to their hospitals and to their healthcare systems. I want to thank them for the tangible support they are offering ERN members.

“However, to fully unlock the potential of ERNs we have to make sure that hospital managers, with our support, co-ordinate their efforts.”

The third challenge underlined by the Health Commissioner related to the selection and integration of new members in the 24 current ERNs. He said: “Highly specialised centres not included in the first approved networks have the opportunity to apply to participate in the work of approved ERNs. In this regard the Commission is planning to launch a new call towards the end of this year.

“We need to ensure that new members bring new knowledge to the ERNs and increase their geographical coverage so that more patients have access to the ERNs in their own country. ERNs need to become stronger, more productive and more readily accessible.”
He also stressed the need to further link ERNs to other important EU projects in the future, such as the European High Performance Computing or the European research infrastructures.

He concluded: “ERNs are best placed to facilitate large clinical studies to improve understanding of diseases and support development of new care models and innovative medical solutions.

“In the future, we can use ERNs as backbone for building a European Health Data Eco-system and initiating better networking between and within member states’ healthcare systems.”

The New Modalities ecosystem

Like the Finnish Network for Rare Diseases, the New Modalities ecosystem is leading the way when it comes to research into rare diseases. The ecosystem is a multidisciplinary collaboration combining high-level academic knowledge with drug discovery and development, and, among other objectives, aims to discover novel and much-needed biomarkers and diagnostic methods for rare diseases, particularly those in the Finnish disease heritage. It has been set up by Finnish pharmaceutical company Orion Corporation and is supported through funding from Business Finland.

The New Modalities ecosystem has been created on the understanding that the potential target proteins of some diseases are unreachable for traditional small molecular drugs. The team of experts and academics involved in the New Modalities ecosystem is working on finding new ways for chemical modifications of antibodies to apply them as carriers for the tissue and cell-specific delivery of drugs. The platform aims to develop steadily automated synthetic strategies for large biomolecular hybrids, which could then be extended further for the library synthesis.

The University of Helsinki is just one of the institutions to be taking part in and benefitting from the New Modalities ecosystem. There, the research of Academy Professor Anu Wartiovaara and Professor Anna-Elina Lehesjoki is focusing on the rare diseases mitochondrial recessive ataxia syndrome (MIRAS) and progressive myoclonus epilepsy. One of out of every 70-80 Finns is believed to carry mutations of one of these diseases.

“Our research clarifies molecular characteristics of these disorders, both disease-specific and shared ones. We aim to discover exact metabolic pathways contributing to disease progression and to use this information, in close collaboration with industry, to improve diagnostics and develop new treatments, also for common degenerative diseases,” say the professors.

Their research will receive more than €2.1m in funding from Business Finland over the next three years.

The New Modalities ecosystem can only be a good thing for Finland and will undoubtedly increase the level of knowledge, understanding and research on rare diseases. Finding pharmaceutical treatment for a rare disease is incredibly complex and requires all the R&D possible, making programmes such as these absolutely vital for the health and futures of millions of patients worldwide.


One of the 24 ERNs, ERN RITA – European Network on Rare Primary Immunodeficiency, AuToinflammatory and Autoimmune diseases – brings, according to its website, a ‘unique opportunity to cross-fertilise diagnostic and therapeutic advances, shared approaches to management and economies of scale across the three streams, given the common set of challenges and opportunities arise:

Each individual disease is caused by genetic and/or functional defects of immune cells and thus requires immunological expertise to understand pathomechanisms and devise novel therapeutic, and Genome-wide analysis platforms and functional immune assays are rapidly developing diagnostic tests shared across all subthemes. These complex investigations cannot be available in all centres and a network approach is vital to ensure uniform patient access and reliable accredited results.’

ERN RITA adds: ‘Immunological therapies are being discovered and implemented rapidly. Polyvalent immunoglobulin therapy has revolutionised the outlook for antibody deficient patients, specific anti-cytokine (anti TNF, anti IL-1 etc.) treatments, have transformed the lives of patients with rare autoimmune and autoinflammatory conditions, and stem cell and gene-based therapies originally for PID are now being applied for all the diseases covered by the proposed network and for the first time enable patients to be completely cured with no need for ongoing medical care.’

The ERN’s mission is:

  • To provide state-of-the-art comprehensive clinical care for children and adults with rare immunodeficiency, auto-inflammatory and auto-immune disorders
  • To ensure every patient across Europe has equal access to excellent expertise and care
  • To establish sustainable alliances with European centres
  • To improve diagnosis and therapy for patients with rare immunodeficiency, auto-inflammatory and auto-immune disorders
  • To train future leaders in the field, securing sustainability in an international perspective
  • To provide a platform for research.

Pharmaceuticals for rare diseases

According to the US Food and Drug Administration, only 5% of rare diseases have a treatment. The issues which arise when creating new pharmaceutical treatments for rare diseases centre around the complexity of the multitude of proteins which may be required at specific times. However, identifying a monogenic target that represents an unsatisfied need provides a manageable entry into gene therapy development.

Other issues with creating life-changing treatments for patients with rare diseases is the lack of medical history surrounding the disease. The small patient population with the disease opens up issues surrounding the lack of crucial information that is needed to successfully and safely develop a drug/treatment around the way the disease works. If a pharmaceutical company does not understand the disease, they can not develop a drug to treat it. In some cases, there are rare diseases that are undiagnosed, which creates additional problems.

The most common difficulties that have been identified when it comes to diagnosing and treating rare diseases are as follows:

  • It may take a long time, even years, for the diagnosis to be made, because generally the disease is not recognised in basic healthcare
  • Finding appropriate care and rehabilitation is not self-evident; this is because of the difficulty in finding personnel with experience in these specific matters
  • Language barriers are often a problem, particularly in medicine, and very little information on the significance of a given disease at different phases of one’s life is available in a multitude of languages.

The Finnish Network for Rare Diseases

With the lack of research into many rare diseases, it is imperative that in order to find treatments, more research needs to take centre stage. Finland is leading the way in treatments for rare diseases with the operation of the Finnish Network for Rare Diseases, which brings together patients, professionals, experts in the Finnish health and welfare system, and decision makers.

The Finnish Network for Rare Diseases creates a link between all these different types of people, co-operating nationally and internationally whilst participating in finding channels of influence at both national and EU-level.

The members of the Finnish Network for Rare Diseases include:

  • Finnish Association of Ultra Rare Diseases
  • Finnish Central Organisation for Skin Patients
  • Finnish CP Association
  • Finnish Deafblind Association
  • Finnish Epilepsy Association
  • Finnish Heart Association
  • Finnish Kidney and Liver Association
  • Finnish Patient Association.

The network brings together a lot more members than the above list represents, and it exemplifies the importance of having experts and associations from all of these disciplines. Together, all of these network members can reach a greater audience for public awareness; having a strong network of passionate and informed people generates a better opportunity to influence decision makers. Having the ability to share information and knowledge between all of the different groups of people will enhance abilities to diagnose rare disease patients and develop treatments.

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