When rare diseases have become stars

It took a half-century for rare diseases to come out of the shadows. They are now a wellspring for scientific research and basic and clinical research is helping patients everywhere. Dr. Ségolène Aymé, Research Director Emeritus and founder of the website Orphanet helps us understand the reasons behind this amazing rise to stardom.

Ségolène Aymé, Research director at Inserm SC11 'Information on rare diseases', Director of the Orphanet web portal and member of the monitoring committee for the national rare diseases plan. Doctor, geneticist and epidemiologist, Paris - © Inserm, F. Guénet

Ségolène Aymé, Research director at Inserm SC11 'Information on rare diseases', Director of the Orphanet web portal and member of the monitoring committee for the national rare diseases plan. Doctor, geneticist and epidemiologist, Paris

"Millions of people suffer from rare diseases and they are a goldmine for medical research. They are a wonderful resource for improving our understanding of living mechanisms and there is an unprecedented interest in the academic and industrial community that is leading to the emergence of new treatments." The scientific community united on the significance of these diseases.

They have come quite a long way in 50 years! In the 1960s, patients suffering from these pathologies (each of which affects fewer than one person in 2,000) were basically left to their own devices. Apart from geneticists, not many people were interested in these illnesses because they are so rare. Only a handful of clinicians were routinely reporting genetically transmitted cases in databases like OMIM (Online Mendelian Inheritance in Man) in the United States or Gendiag, a database Inserm created in 1974 that 20 years later went on to become Orphanet. So, how did these diseases eventually wind up taking centre stage?

The rise of the Human Genome Programme

The story actually began in 1990 in the midst of the genetic boom. The global community decided to launch the Human Genome Programme to map out genes in chromosomes. At that very moment, everyone began looking at rare diseases because they are so often linked to the transmission of a single defective gene. From then on, families carrying these pathologies became the crucial link in identifying the mutated gene, finding it in the chromosomes and, most importantly, clarifying its role based on the symptoms observed. France, and Inserm in particular, the Jean Dausset Foundation and the French Anti-Myopathy Association Telethon greatly advanced the programme. "That step catapulted the rise of rare diseases in research for their scientific significance," says Ségolène Aymé.


Human karyotype. The chromosomes, in pairs, have characteristic colour bands - © Inserm, Alpha Pict, D. Caro

Human karyotype. The chromosomes, in pairs, have characteristic colour bands

Facts about rare diseases
Diseases are classified as rare when they theoretically affect fewer than one person in every 2,000, but most of them only strike a few patients worldwide. Over 6,000 of these pathologies are known today and another 200-300 are characterized every year. So they affect several million people around the world, including about 3 million in France. Two-thirds of these diseases manifest in childhood, which makes them paediatric illnesses. Most of them are genetic and the remainder are autoimmune diseases, rare cancers or infectious diseases. Found in all sectors of medicine, there is a broad spectrum of these diseases and they are often serious, chronic and progressive.

Given the fast-paced advance of characterizing these diseases, in 1997 Ségolène Aymé took advantage of the newly introduced Internet and the momentum it generated to create a massive Inserm database available to everyone: Orphanet. It references all the known rare diseases, provides documentation on them and contact information for experts on each pathology to create closer ties between researchers and clinicians. The database started out with about 2,000 files and now lists over 6,000 pathologies with hundreds more are added every year. Suffice it to say that Orphanet has become a global reference in rare diseases. Some 50 researchers maintain and update it regularly based on scientific publications.


The age of cloning and policy decisions

Inserm stand at Medec 2001. Home page for the Orphanet server, database for rare diseases and orphan drugs - © Inserm, M. Depardieu

Inserm stand at Medec 2001. Home page for the Orphanet server, database for rare diseases and orphan drugs

In the early 2000s, the introduction of cloning techniques further advanced knowledge about these diseases. These techniques essentially made it possible to produce countless copies of the gene so it could be studied, which led to a broader understanding of a vast array of mechanisms. "The research really took off at that point. Inserm and others were publishing very compelling research," explains Ségolène Aymé. "Researchers realized that by studying rare diseases they could describe genes, proteins and fundamental biological mechanisms to understand living beings and more common illnesses."

Thanks to highly incentivising legislation, alongside this progress came major therapeutic breakthroughs. Starting in 2000, a few years after the United States, Europe effectively introduced a system to motivate the scientific community called the Orphan Medicinal Products Regulation. The law gives manufacturers that commit to developing therapeutic solutions a return on their investment even though these markets can be very small. It has resulted in 70 new products since it was introduced.

Since 2004, the French ministry in charge of health has also been providing support for rare diseases after they were made one of the five priorities in the public health law. The government launched two consecutive plans from 2005 to 2008 and then 2011 to 2014 to improve how treatments and research are organised. Patients have benefited from a number of advances, like funding for 131 new rare disease resource centres, backing for a public information service called Maladies Rares Info Services, the recently introduced Rare Diseases Foundation for scientific cooperation and grants for rare disease cohorts.

Hugues Parrinello, at the GenomiX (IBISA) platform, high-speed sequencing of DNA microarrays. Institut de Génomique Fonctionnelle (IGF - Functional Genomics Institute), Montpellier - © Inserm, P. Latron

Hugues Parrinello, at the GenomiX (IBISA) platform, high-speed sequencing of DNA microarrays. Institut de Génomique Fonctionnelle (IGF - Functional Genomics Institute), Montpellier

"We have now entered the third era, which is high-speed sequencing," suggests Ségolène Aymé. "Every patient will soon be able to find out their genetic profile. This will make it possible to accurately identify the mutation or mutations causing the disease and provide the best treatment possible." This new frontier will be crossed in the coming years as molecular genetic platforms are gradually introduced into the health system and an upcoming national centre for very high-speed sequencing opens.

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