From rare to frequent: the importance of conducting research on genetic diseases

How does the study of the 7,000 to 9,000 rare genetic diseases provide essential knowledge for the development of therapeutic leads for much more frequent diseases?

Published on 23.02.2021

Research Acceleration

Three million French people are affected by rare diseases, i.e. one person in 20, some of them only a few dozen or hundreds of patients. However, by studying rare genetic diseases and the genes involved, this knowledge not only benefits the affected patients, but also, by highlighting the function of these genes, it can help decipher general mechanisms, often not yet described. This may also allow us to take a fresh look at much more common diseases. While the study of all these rare diseases remains a titanic task, it is essential to carry it out, not only to open up new therapeutic avenues for the patients concerned, but also to imagine new ones for other pathologies.

Oscillating between the very common and the very rare, even the very exceptional, is the daily work of the Imagine Institute's research. Our teams are working on sickle cell disease, the most common genetic disease in the world, as well as on pathologies that concern only a few children, but which can open up avenues of understanding in common diseases, when the mechanisms are linked.  

Prof Stanislas Lyonnet , Director of Institut Imagine

"Thus, discoveries made on rare pathologies can provide knowledge or therapeutic leads on common diseases. This is all the intellectual and operational agility of a University Hospital Institute (IHU) combining medical, scientific and even industrial expertise," emphasizes Professor Stanislas Lyonnet, Director of Institut Imagine (Inserm/University of Paris/AP-HP), located at the Necker-Enfants malades AP-HP hospital.

For example, very recently, the work of Inserm researcher Laurent Abel and Jean-Laurent Casanova, co-directors of the Human Genetics of Infectious Diseases Laboratory at Imagine, has shown that knowledge of exceptional immune deficiencies, revealed by common bacterial or viral infections, could help to understand the most severe clinical forms observed in Covid-19. They were thus able to highlight the genetic or immunological mechanisms linked to autoantibodies responsible for 15% of the severe forms of SarsCov-2 infection.

International Rare Diseases Day, February 28, 2021, is an opportunity for Imagine to revisit this work and to highlight research that illustrates the links between rare genetic diseases and common diseases.

From achondroplasia to osteoarthritis and osteoporosis

Achondroplasia, the most common form of dwarfism, currently affects about 8,000 people in France. It is due to abnormalities in growth cartilage and bone formation. In 1994, Laurence Legeai-Mallet co-discovered the gene responsible for achondroplasia, the FGFR3 gene. Excessive production of the FGFR3 protein alters ossification, the mechanism that transforms cartilage tissue into bone. The discovery of the mutated gene and the work that has been developed has led to a better understanding of the mechanisms regulating cartilage homeostasis and bone formation. This research has led to the development of several therapeutic options. Today, five clinical trials are in development for achondroplasia. In this pathology, cartilage and bone damage can be related in certain aspects to two frequent adult pathologies: osteoarthritis, a degradation of articular cartilage that is sometimes disabling and very painful, and osteoporosis, which causes great fragility of the bones.

"There is no direct treatment for these two common conditions. However, our research aimed at identifying gene signatures and cellular and molecular mechanisms, and our development of cellular and animal models for achondroplasia could provide therapeutic solutions for osteoarthritis and osteoporosis," concludes Dr. Laurence Legeai-Mallet (Laboratory of Molecular and Pathophysiological Basis of Osteochondrodysplasia atInstitut Imagine).

From genetic immune deficiencies to lymphomas or autoimmune diseases

Sylvain Latour's team is studying the mechanisms of the immune response involved in the control of infection by the Epstein Barr Virus (EBV), which is the main virus in humans responsible for several cancers, the most common of which is lymphoma.

"Thanks to the study of two very rare diseases, we were able to propose therapeutic approaches for more frequent diseases, such as lymphomas or autoimmune diseases," explains Dr. Sylvain Latour, Director of the Lymphocyte Activation and Epstein-Barr Virus Susceptibility Laboratory.

In the first case, his team recently showed that CTPS1 enzyme deficiency in humans leads to a high susceptibility to viral infections, particularly EBV infection, highlighting the crucial role of proliferation and expansion of activated T cells during immune responses. Based on this discovery, Step-Pharma, a spin-off from Imagine, was created to develop CTPS1 inhibitors that could represent a new treatment for diseases caused by excessive and inappropriate T cell proliferation such as T lymphoma, transplant rejection or autoimmune diseases. In the second case, the CD70 gene has been identified by the team as responsible for susceptibility to Epstein-Barr virus infection and the development of B lymphomas when defective in children. This defect is also found in some adult B lymphomas. The team's work has shown that the lack of expression of the CD70 protein on the surface of lymphoma cells results in an ineffective immune response against these cells. This work has led to the proposal of a new gene therapy aimed at re-initiating an anti-tumor immune response for the treatment of certain lymphomas.

The importance of conducting research on even very rare genetic diseases

Emphasis is often placed on the small number of patients involved in research on genetic diseases, but there is no shortage of examples to show that this knowledge benefits everyone. For example, research on families affected by rare cancers has led to the identification of cancer susceptibility genes involved in DNA repair or cell division. The detailed knowledge of cancer triggers has opened up new therapeutic avenues, such as targeted therapies. As another example, a therapeutic class developed to treat the rare disease of hypophosphatasia is being used to treat osteoporosis.

These examples illustrate the importance of conducting research on genetic diseases for the benefit of all. The International Rare Diseases Day, February 28th, is an opportunity to remind us of this.

Learn more about genetic diseases, two days of web-conferences at Imagine

On the occasion of this international day, Institut Imagine is organizing a series of web-conferences on February 27 and 28, 2021, and invites the public to discuss various themes such as sickle cell disease, rare epilepsy, immune deficiencies, inflammatory bowel disease, mitochondrial disease, congenital heart disease, language disorders, genetic eye diseases, and genetics explained to children. The detailed program is available here.