Imagine, the leading European research center for genetic diseases

Its director, Stanislas Lyonnet, explains to us what lies behind the driving force of this unique institute, which brings doctors and researchers together with young patients to understand genetic diseases and invent treatments. In the future, those treatments will cure those young patients.

What place do genetic diseases hold within rare diseases?

Stanislas Lyonnet : 80% of diseases considered to be rare are of genetic origin. Rare diseases affect fewer than 1 in 2,000 people. Taken separately, these diseases are highly rare, even exceptional, but throughout Europe, they affect 35 million people. In France, 3 million French people are affected, nearly one in 20.

Genetic diseases occur because of an alteration in the base entity which makes up our body, the cell, at the level of our genome. Once a gene is affected, it is followed by a defective or absent production of protein. Yet, these molecules are supposed to fulfill specific functions in the cells. The damage of one single gene affects multiple organs in a more or less harmful way, impacting the lives of the people concerned. However, the mechanisms of the same rare disease or the same type of disease can vary. For example, in 2001, Corinne Antignac's team at Imagine was the first to highlight a genetic origin of steroid-resistant nephrotic syndrome. In these patients, the kidney does not successfully play its role of sorting macromolecules. As a result, proteins that are normally retained in the blood accumulate in the urine. Since then, more than 20 other genes that could be at the origin of this syndrome have been identified.

 

What value is provided by knowledge of the genetic anomaly in question?

SL : Identifying the defective gene is essential for continued research to better understand the disease. Researchers can then explore the cellular mechanisms involved and above all try to restore them. It is the same principle that prevailed when Imagine was created: generate expertise synergies between doctors and researchers to advance research in genetic diseases and cure them.

Even if there have been significant improvements at the level of rare diseases, young patients and their family sometimes arrive at Imagine after months, even years, of misdiagnosis. Therefore, we make every effort to identify the origins of the disease. Often the families explain to us that, to them, arriving at Imagine is their last chance. Filled with doubt and often feeling discouraged, at Imagine they find a place where doctors and researchers will do everything, above all, to give a name to the disease that their child suffers from, and the hope of these families is renewed.

 

And treatments have already been developed at Imagine?

SL : There is still a lot to be done to treat all children, but each cure proves to us that we are on the right track. In 2017 and 2018, under the leadership of Pr. Marina Cavazzana, gene therapy proved its potential to treat children with two forms of hereditary anemia: sickle-cell anemia and beta-thalassemia. The patients who have had their defective gene repaired, as this is the principle of this treatment, now produce enough hemoglobin and no longer need transfusions. Trials are also underway in children and teenagers with dystrophic epidermolysis bullosa, a skin disease which can lead to loss of sight, fusion of the fingers and toes, as well as cancer. They follow the work of Alain Hovnanian's team.

In interferonopathies, the work of Frédéric Rieux-Laucat's team and Yanick Crow's team at Imagine has deciphered defective cellular mechanisms and ways to counteract them via JAK1/2 inhibitors. Thanks to these discoveries, Fanny, who arrived at the Institute in 2014 presenting with lesions almost stopping her from walking, and bouts of pain causing her to vomit, now lives like all other children her age. In only 3 years, the expertise synergies between doctors and researchers at Imagine have enabled a new disease to be outlined, to understand the genetic cause, the mechanism and develop a treatment. That is the strength of integrating treatment and research at Imagine: never give up, look for good collaborations, innovate without stopping to conquer genetic diseases.

Other children like Fanny have benefited from Imagine’s great potential. However, genetic origins are still unknown for nearly half the children with a genetic disease and 95% of genetic diseases have no specific cure. This observation can only encourage us to continue the fight, especially as the first results obtained already show that we are on the right track.

 

Examples of success

Since its creation, researchers and doctors at Imagine have not stopped advancing knowledge of genetic diseases, and for some, treatments have already emerged. Today research continues so that more children are diagnosed.

 

Gene therapy

Curing children with two forms of hereditary anemia: sickle-cell anemia and beta-thalassemia. Patients treated with gene therapy now produce enough hemoglobin and no longer need transfusions.

 

Interferonopathies (dermatomyositis, Aicardi-Goutieres syndrome)

The collaboration of Frédéric Rieux-Laucat, Yannick Crow and Bénédicte Neven's teams have enabled the discovery of the cellular mechanisms involved and ways - JAK1/2 inhibitor - to block their effects. In patients, we notice improved conditions overall and the almost complete disappearance of skin lesions.

 

Achondroplasia (disease which affects 1 child in 15,000 and which clinically results in a rhizomelic dwarfism, short limbs, a narrow rib cage and a macrocephaly)

Laurence Legeai-Mallet's team demonstrated that the mutation of the FGFR3 gene leads to its permanent activation and stunted growth of the bones. The next step is to uncover molecules capable of deactivating FGFR3. Today, one of the molecules tested at the preclinical stage is subject to a phase III clinical trial, the last stage of clinical research before the marketing authorization.

 

Indolent systemic mastocytosis (the accumulation and proliferation of a type of white blood cell, mastocytes, in the marrow, liver, bones, digestive tract, lead to allergic and inflammatory reactions)

Patients suffer with fatigue, depression, cognitive disorders, skin lesions. And in the most virulent forms, it is followed by hepatic fibrosis, anaphylactic shock, etc... Olivier Hermine's team has demonstrated that the deregulation of the signaling pathway is c-kit-dependent in this disease, which led to clinical trials reducing symptoms with an inhibitor of the c-kit pathway, mastinib.

 

Skin disease

Dystrophic epidermolysis bullosa is characterized by the formation of bubbles and ulcerations of the skin, of which the consequences can go as far as loss of sight, fusion of the fingers and toes, and cancer. Alain Hovnanian's team develops ex vivo gene therapy clinical trials for recessive forms.

The same team has uncovered the gene responsible for Darier disease, a hereditary skin condition. The ATP2A2 gene encodes a calcium pump, which leads to a deregulation of this in the cells.

 

Friedreich ataxia (neurodegenerative disease causing problems with balance and co-ordination of voluntary movements)

Agnès Rötig's team has highlighted an accumulation of iron in some cells. A clinical trial is expected to start in 2019 to counteract this effect.

 

Steroid-resistant nephrotic syndrome

The team of Corinne Antignac, director of the hereditary kidney diseases laboratory at Imagine, professor at Necker-Enfants Malades and Paris Descartes, discovered the 1st gene at the origin of this syndrome in 2001. Since then, more than 20 genes have been identified (including a new one in her team in 2019).