Neurodevelopmental Disorders in Children: A New Gene Called Into Question

ADN© Double helix DNA – National Human Genome Research Institute, National Institutes of Health.

In the face of childhood neurodevelopmental disorders, how can we get out of the therapeutic “dead end”? The answer could well be found in the genes of the proteasome – an intracellular mechanism that is responsible for removing defective proteins from the cell. A research team from Inserm, CNRS, Nantes Université and Nantes University Hospital, at the Thorax Institute and in collaboration with international teams, studied the genome of 23 children with neurodevelopmental disorders. What they found were fifteen mutations in the PSMC3 gene of the proteasome, which may be involved in their disease. This research, published in Science Translational Medicine, opens up new research perspectives in order to better understand these diseases and identify treatments.

The origin of neurodevelopmental disorders in children remains difficult to identify, with patients and their families often having to wait several years for a diagnosis.

A research team from the Thorax Institute (Inserm/CNRS/Nantes Université/Nantes University Hospital), led by Stéphane Bézieau, Head of the Medical Genetics Department at Nantes University Hospital, has been working on the genetics of neurodevelopmental disorders in children for several years. In particular, its research has led to the identification of the role of a gene called PSMD12 in a childhood neurodevelopmental disease. This gene is expressed in a large complex of proteins located in the cells, which is called the proteasome.

The proteasome acts as a kind of “garbage collector” within the cell. By eliminating the defective proteins it contains, the proteasome plays a decisive role in a large number of cell processes. Alterations that may appear on some of its constituent genes are likely to affect its ability to break down defective proteins. Their accumulation results in the development of a wide variety of pathologies.

In new research[1] in collaboration with international teams, the team continued to explore the links between proteasome gene mutations and neurodevelopmental diseases. This time it was more specifically interested in the proteasome PSMC3 gene and its involvement in the neurodevelopmental disorders of 23 young European, U.S. and Australian patients with neurological symptoms (delayed speech, intellectual disability, or behavioral problems) frequently associated with abnormalities of the face and malformations of the skeleton, heart and other organs.

Thanks to the full sequencing of the genome of these patients, the researchers have revealed fifteen mutations in the PSMC3 gene likely to explain the origin of the symptoms.

“It quickly became apparent that the cells of patients with a defective PSMC3 gene were literally overloaded with unnecessary and toxic proteins,” explains Frédéric Ebstein, Inserm researcher and first author of the study.

He compares this phenomenon to that observed in some age-related neurodegenerative diseases, such as Alzheimer’s or Parkinson’s.

“The discovery of the involvement of a second gene in childhood neurodevelopmental disorders provides unprecedented insight into this group of rare diseases that had been unknown until recently, clarifies researcher Sébastien Küry, an engineer at Nantes University Hospital, who co-signed this research. This research, combined with the team’s recent discovery of other genes involved [but not published as yet, ed.], opens up major perspectives in the understanding of this group of neurodevelopmental diseases as well as prospects for their treatment,” he concludes.


[1]This research is supported by the French National Research Agency (ANR), the European Union (European Joint Programme on Rare Diseases), and the insurance company AXA.

Who are the first ancestors of present-day fish?

poisson arowana

Arowana fish © Pixabay

What is the origin of the ancestors of present-day fish? What species evolved from them? A 50-year-old scientific controversy revolved around the question of which group, the “bony-tongues” or the “eels”, was the oldest. A study by INRAE, the CNRS, the Pasteur Institute, Inserm and the Muséum National d’Histoire Naturelle, has just put an end to the debate by showing through genomic analysis that these fishes are in fact one and the same group, given the rather peculiar name of “Eloposteoglossocephala”. These results, published in Science, shed new light on the evolutionary history of fish.

Understanding the evolutionary history of species through their relatedness is an essential issue and regularly the subject of scientific controversy. One of them concerns the position, in the tree of life, of the three oldest groups of teleost fishes, which appeared towards the end of the Jurassic period (from 201.3 to 145 million years ago) and which include most of our present-day fishes. These three groups consist of the “bony-tongues”, the “eels” and a group that unites all other species of teleost fishes. Early classifications in the 1970s, based solely on anatomical criteria, had classified the “bony-tongues” as the oldest group. Modern classification approaches, however, based on the use of DNA sequences to reconstruct the evolutionary history of life, placed the “eels” as the oldest group. Ever since, controversy has ensued.

What if both hypotheses were wrong?

To investigate this question, scientists sequenced the genomes of several species in the “eel” group, including the European eel and the giant moray eel. They analysed the DNA sequences to gain insight into the structure and organisation of the genes within the genome. They were thus able to reconstruct, in a very reliable way, the relationships between the different teleost fishes, which led to an end of the controversy without winners or losers: neither hypothesis was valid!

Surprisingly, scientists have discovered that the two groups of “eels” and “bony-tongues” are in fact one and the same in terms of evolutionary history. The researchers have named this group “Eloposteoglossocephala”. These results put an end to more than fifty years of controversy about the evolutionary history of the main branches of the teleost fish tree of life.

They shed new light on the evolutionary history of fishes and the understanding of evolutionary processes.

Who are the first ancestors of present-day fish?


Teleost fish trees of life representing the two hypotheses of the controversy and its resolution in the present study


A Bacterium to Protect the Microbiota from the Harmful Effect of Food Additives

microbiote colon

Section showing the interaction of the microbiota and the intestinal epithelium in the colon. In blue, the mucus secreted by the intestinal epithelium in protection against the microbiota. In pink, the epithelial cell nuclei. © Noëmie Daniel/Inserm

Emulsifiers are food additives that are used to improve texture and extend shelf life. They are found in many processed products (ice cream, packaged cakes, sauces, etc.) despite having demonstrated harmful effects on intestinal balance. In a new study, scientists from Inserm, CNRS and Université Paris Cité at Institut Cochin in Paris sought to counteract these effects by using Akkermansia muciniphila, a bacterium naturally present in the intestine, to repopulate and thus strengthen the intestinal epithelium. The addition of this bacterium to the gut microbiota is thought to prevent the damage caused by the consumption of emulsifiers. These data, published in Gut, confirm the growing potential of Akkermansia muciniphila as a probiotic.

Emulsifiers are consumed by millions of people every day and are among the most widely used additives in the food industry. Something that is not surprising given that they improve the texture of foods and extend their shelf life. For example, emulsifiers such as lecithin and polysorbates ensure the smooth texture of mass-produced ice cream and prevent it from melting too quickly once served.

Previous studies by the team of Benoît Chassaing, Inserm researcher at Institut Cochin (Inserm/CNRS/Université Paris Cité), have shown the consumption of certain emulsifiers to lead to alterations of the gut microbiota[1] and how it interacts with the digestive system. Such alterations lead to chronic gut inflammation and metabolic dysregulation. More specifically, this research has shown the consumption of food emulsifiers to induce the ability of certain elements of the microbiota to come into close contact with the epithelium, which is the first line of defense of the digestive tract and usually sterile.

 In this new study, the researchers wanted to counteract the harmful effects caused by the consumption of emulsifiers by reinforcing the intestinal epithelium. To do this, they focused more specifically on the bacterium Akkermansia muciniphila, which, being naturally present in the intestine has already been shown to have an impact on the interactions of the microbiota with the rest of the body.

It is also known that the quantity of this bacterium is reduced when emulsifiers are consumed.

In the study, groups of mice were fed emulsifying agents as part of their diet, which for some of them was supplemented with a daily dose of Akkermansia muciniphila. The scientists saw that while the consumption of food emulsifiers was sufficient to induce the chronic inflammation associated with metabolic alterations and high blood glucose, the mice receiving Akkermansia muciniphila were totally protected against such effects. The administration of Akkermansia muciniphila was also sufficient in preventing all molecular alterations normally induced by the consumption of emulsifying agents, including the encroachment of bacteria into the wall of the epithelium.

“This research supports the notion that using Akkermansia muciniphila as a probiotic could be an approach to maintaining metabolic and intestinal health in the face of modern stressors such as emulsifiers that promote chronic gut inflammation, and the resulting harmful consequences. Furthermore, this suggests that colonization of the intestine with Akkermansia muciniphila could be predictive of individual propensity to develop intestinal and metabolic disorders following the consumption of emulsifiers: the greater the presence of the bacterium, the more likely the individual is protected from the harmful effects of food additives on the microbiota,” explains Chassaing, the last author of the study.


[1] All of the microorganisms – non-pathogenic (commensal) bacteria, viruses, parasites, and fungi – that live in the intestine.

A New Gene Therapy Strategy for Sickle Cell Disease and Beta-Thalassemia

Sickle-shaped red blood cells (sickle cell disease) © Inserm/Anne-Marie Chevance de Boisfleury


Both sickle cell disease and beta-thalassemia are genetic disorders that affect hemoglobin, and as such are categorized as beta-hemoglobinopathies. A team of scientists from Inserm, Université Paris Cité and the Paris Public Hospitals Group AP-HP at the Imagine Institute has shown the efficacy of a gene therapy approach to treat these two disorders. The principle is to reactivate in patients the production of fetal hemoglobin, a protein whose expression usually ceases after birth. In a study published in Nature Communications, the research team describes a promising approach for future therapeutic applications.

Sickle cell disease and beta-thalassemia are genetic disorders known as beta-hemoglobinopathies. They are caused by mutations on chromosome 11 of the gene responsible for the production of beta globin, a constituent protein of hemoglobin which is the main component of red blood cells.

In sickle cell disease, the structure of beta globin is altered, affecting the integrity of red blood cells and leading to anemia, very painful local obstructions of the blood circulation (vaso-occlusive crisis), and gradual organ damage. In beta-thalassemia, beta globin production is drastically reduced, causing hemoglobin deficiency and leading to severe anemia.

In the 1970s, researchers observed that rare individuals with mutations specific to each of these conditions did not develop the disease. What was it they had in common? They were all carriers of compensatory mutations on another chromosome 11 gene, which stimulated the production of fetal hemoglobin (gamma globin). This protein that usually ceases to be produced at the end of fetal life is able to advantageously replace the defective adult beta globin to form healthy hemoglobin, thereby ensuring the production of perfectly functional red blood cells in sufficient quantities.

A research team led by Annarita Miccio, Inserm researcher at the Imagine Institute (Inserm/Université Paris Cité/Paris Public Hospitals Group AP-HP) conducted a series of in vitro experiments to determine the most effective strategy for stimulating fetal hemoglobin production, using gene therapy to reproduce these beneficial mutations for treatment purposes. The most effective approach was to insert a genetic mutation that generates, in red blood cells, a molecular mechanism with the dual advantage of stimulating fetal hemoglobin production and blocking the mechanism that naturally inhibits that production.

Furthermore, the researchers have shown in animals that this strategy is effective over the long term, which is a very important finding in the context of therapeutic application.

There is still a long way to go before this new gene therapy approach can be used in a clinical setting,” explains Panagiotis Antoniou, first author of the study, for example, we need to optimize the protocol in order to genetically modify more red blood cells, as only 60% are done so with the current protocol. Nevertheless, our research is paving the way for the clinical development of a safe and innovative treatment for patients with beta-hemoglobinopathies, with the objective of improving their quality of life,” concludes the researcher.


Sickle cell disease, which affects 5 million people worldwide, is the leading genetic disorder worldwide and the most common in France. Every year, about 100,000 children worldwide are born with a severe form of beta-thalassemia. In order to continue to support the advances of research in fighting rare diseases, the 2022 edition of the Telethon (only available in French) will be broadcast over a 30-hour period on December 2-3, on France Télévisions.

Towards a New Drug Class in the Treatment of Type 2 Diabetes

Mouse visceral adipose tissue fluorescently labeled with AdipoRed. Nuclei are stained blue. © Vincent Marion.

Type 2 diabetes is a major public health problem that affects millions of people worldwide. Developing new drugs to help better treat its underlying causes is therefore a research priority. In a new study coordinated by Inserm researcher Vincent Marion in collaboration with the University of Birmingham (UK), Monash University (Australia), and along with Alexander Fleming, former senior endocrinologist at the US Food and Drug Administration (FDA), the scientists have developed PATAS, a peptide that is part of a new class of antidiabetic drugs. PATAS can correct the metabolic abnormalities leading to type 2 diabetes and its associated comorbidities which include insulin resistance[1]. PATAS works by specifically targeting the adipocytes (fat cells)[2], restoring glucose entry and thus correcting and re-establishing the metabolic physiology of the adipose tissue. The teams hope to set up a clinical trial soon to test this new therapy. Their study has been published in the journal Diabetes.

Diabetes mellitus is a chronic condition that affects 537 million people worldwide, with the majority affected by type 2 diabetes. The prevalence of type 2 diabetes, which is characterized by high levels of glucose in the blood (see box), has been increasing for decades due to population aging, inactivity, and poor diet. The age of onset is also decreasing, and although the disease is considered to be an “adult disease”, it is now seen frequently in adolescents and children.

Available drugs treat the consequences of type 2 diabetes by focusing mainly on lowering blood glucose; they do not target the underlying biological mechanism that causes the disease.

Despite the urgency for developing new and more effective treatments, there have been no disruptive therapeutic innovations to reach market in over a decade.

And this is precisely the objective of the research led by Inserm researcher Vincent Marion and his team at the Medical Genetics Laboratory (Inserm/Université de Strasbourg). In a recent study in collaboration with the University of Birmingham and Monash University, the scientists have developed a product called PATAS in a new class of diabetes drugs called “Adipeutics” (for therapies that specifically target the adipocytes).

Their study, conducted on animal models, shows that this new therapy specifically restores glucose uptake in the adipocytes, resulting in the treatment of insulin resistance with beneficial effects on the whole body. This is made all the more promising by the fact that treating insulin resistance has the potential to address not only type 2 diabetes but a large array of serious medical conditions that result from this resistance.

Type 2 diabetes in brief

Diabetes mellitus is characterized by excessive blood glucose levels over a prolonged period of time: this is known as hyperglycemia.

Hyperglycemia is caused by a reduced sensitivity of the cells, particularly those in the liver, muscle, and adipose tissue, to insulin. This is known as “insulin resistance.”

Insulin is a hormone produced by the pancreas whose role is to facilitate the entry of glucose into the body cells as their main source of energy. To meet the increased demand for insulin caused by the cells’ resistance to this hormone, the pancreas produces even more insulin, depleting the body requirements. Insulin production then becomes insufficient and the blood glucose levels rise as a result.

The role of adipocytes

This study follows on from years of rigorous, in depth work carried out in the lab. In previous research, published in Diabetes in 2020, the scientists had identified a new therapeutic target for type 2 diabetes when investigating at an ultra-rare monogenic disease known as Alström syndrome.

The scientists had shown that adipose tissue abnormalities caused by a dysfunctional protein called ALMS1 led to extremely severe insulin resistance associated with early-onset type 2 diabetes in people with Alström syndrome. In animal models, restoring the function of this protein within the adipocytes re-established blood glucose balance.

The teams then went on to focus more closely on ALMS1 and how it interacts with other proteins within the adipocytes. In particular, they have shown that in the absence of insulin, ALMS1 binds to another protein called PKC alpha. The activation of insulin in the adipocytes induces the separation of these two proteins ALMS1 and PKC alpha, resulting in glucose entry into cells. In people with diabetes, who are insulin-resistant, this link between the two proteins is maintained.

Drawing on this knowledge, the scientists have developed the peptide PATAS, which works by breaking the interaction between ALMS1 and PKC alpha – thus restoring insulin signaling in the adipocytes.

In mouse models of diabetes, PATAS has been able to re-establish the normal physiology of the adipocytes by restoring glucose uptake. “Thanks to PATAS, the adipocytes that could no longer access glucose were once again able to absorb it and then metabolize it in order to synthesize and secrete lipids which are beneficial to the entire body. These positive effects are visible in our animal models, with a marked improvement in insulin resistance. Other parameters and comorbidities are also improved, including better blood glucose control and decreased liver fibrosis and steatosis,” explains Vincent Marion.

These promising results in animals have paved the way for the researchers to organize a clinical trial as soon as possible, in order to test PATAS in humans. The successful development of a new class of antidiabetic drugs could have significant implications for public health, not only to treat type 2 diabetes but also many other cardio-metabolic disorders in which dysfunctional adipocytes and insulin resistance are very problematic.

In order to create value from these findings and facilitate the organization of such a trial, Vincent Marion has founded the start-up AdipoPharma SAS.


[1] Insulin resistance is when cells in your muscles, fat, and liver do not respond well to the hormone insulin and can’t use glucose from the blood as their energy source. Insulin resistance is the basis of high blood fats, heart and vascular disorders, metabolic syndrome and type 2 diabetes

[2] Adipose tissue is a set of cells known as adipocytes that store fats.

Scientists discover novel mutation associated with alternating hemiplegia of childhood

hémiplégie alternante de l'enfant (HAE)

The effect of G60R mutation on CLDN-5 expression and localization in CLDN-null cells. © Matthew Campbell, Smurfit Institute of Genetics, Trinity College Dublin

Scientists at Trinity College Dublin and the Institute Imagine at Necker Hospital, Paris, announced a significant advance in our understanding of a very rare condition called alternating hemiplegia of childhood (AHC). This is a devastating condition that can lead to repeated paralysis that affects one side of the body or the other or sometimes both at once. It usually begins to affect children before 18 months of age and to date, only one causative gene has been identified.

Here, scientists in Dublin and Paris have now identified a second gene CLDN5 as being responsible for the condition in 2 unrelated cases of AHC in France. The protein product of this gene, claudin-5, is critical for maintaining the integrity of the blood-brain barrier (BBB). Intriguingly, the mutated form of the protein turns the barrier into a channel that is selective for negatively charged ions. In this regard, the ionic compositions of the brain are likely shifted in these children and this is a key driver of the condition.

“This finding was based on an amazing collaboration with Prof Arnold Munnich’s group at the Institute Imagine in Paris. The identity of these de novo mutations in unrelated children suggests that the barrier is turning into a channel. This is exciting on numerous levels as it is the first report of the BBB turning into a channel, but it also sheds light on the devastating pathology of AHC which may assist in clinical management of patients with this mutation” said Dr Matthew Campbell, Associate Professor at Trinity.

Importantly, the work has implications for our basic understanding of the junctional protein that forms the BBB. As this is the first report of the human BBB becoming a channel, there may be avenues for drug delivery that have never been explored. This will now form the basis of the next steps of the project.

Dr Yosuke Hashimoto, visiting researcher from the Japanese Society for the Promotion of Science (JSPS), and his equally contributing colleague Dr Karine Poirier from the Institute Imagine added: “This exciting project has shed light on a very rare condition affecting children. We are delighted that our work was able to quickly identify the causative mutation for the disease as well as progressing our understanding of the pathology of the disease.”

Commenting on the study, Prof Arnold Munnich from the Institute Imagine in Paris said “We are delighted this work has progressed so quickly and our groups have been able to work very closely to identify the cause of this condition. Studies like this will benefit families and clinicians immensely in the years to come”.

A multidisciplinary team of Geneticists, Neurologists and Radiologists from Ireland and France undertook the study.

The research, published this week in the international journal, Brain was supported by Science Foundation Ireland (SFI), FutureNeuro, Japanese Society for the Promotion of Science (JSPS) and the European Research Council (ERC)

MICA: A New Immune Response Gene That Predicts Kidney Transplant Failure

Histological image of a kidney transplant rejection mediated by antibodies. Sophie Caillard/Jérome Olagne (Inserm U1109).

Although a kidney transplant is the only curative treatment for end-stage kidney disease, the risk of the patient’s body rejecting the graft means that success is not guaranteed. To reduce this risk, physicians are now able to look at a certain number of genetic and immunological parameters in order to evaluate the histocompatibility between donor and recipient – i.e. how compatible their organs and tissues are. Nevertheless, rejections continue to remain common, and many are unexplained. In a new study, researchers from Inserm, Université de Strasbourg and Strasbourg University Hospitals at Unit 1109 “Molecular Immunology and Rheumatology”, and their partners from the Laboratory of Excellence (LabEx) Transplantex, report that the MICA gene is a new histocompatibility gene, in that it helps to better explain and predict the success or failure of a kidney transplant. Their findings have been published in Nature Medicine.

Kidney transplant is currently the best way to treat patients with end-stage kidney disease. In France, an average of around 4,000 kidney transplants are performed each year (around 20,000 in the US). The kidneys mainly come from deceased donors, although the number of kidneys from living donors has been gradually increasing each year over the last two decades.

The possibility of rejection of the graft considered “foreign” by the recipient’s body is currently the main limitation of this procedure. While the use of immunosuppressant drugs[1] helps to reduce the risk, it does not eliminate it completely. “Chronic” rejection, which occurs over the years following the transplant, remains a major problem.

The discovery of the HLA system in the mid-20th century by French researcher Jean Dausset and his colleagues has enabled major advances. It is a set of proteins coded by the HLA genes – proteins which are present on the surface of our cells, particularly white blood cells.

Highly diverse and specific to each individual, this system makes it possible to assess the histocompatibility between donors and recipients – i.e. how compatible their organs and tissues are. The closer the HLA genes between donors and recipients, the lower the risk of rejection.

However, even when donor and recipient HLA genes are compatible, unexplained transplant rejections still occur. This phenomenon suggests that other as yet unidentified histocompatibility genes may play a role.

A role for the MICA gene

Researchers from Inserm, Université de Strasbourg and Strasbourg University Hospitals and their partners from LabEx Transplantex were therefore interested in a gene discovered almost thirty years ago by Seiamak Bahram[2] who coordinated this new research.

This gene, called MICA, codes for a protein expressed on several cell types. Previous studies had already suggested that this gene was important in predicting the outcome of a transplant, but the numbers of patients studied were insufficient (among other methodological limitations) in asserting that it was a histocompatibility gene. Furthermore, these studies did not focus on the entire MICA system, that is to say on both genetics (histocompatibility) and the serological aspects (presence of anti-MICA antibodies in the recipient’s blood).

In this latest study, the team studied MICA in over 1,500 kidney transplant recipients and their donors. Analyses of the MICA gene sequences show that when recipients and donors have a different version of the gene, the survival of the graft is reduced.

Furthermore, the researchers show that these MICA gene incompatibilities are responsible for the synthesis of antibodies directed against the donor’s MICA proteins, which are involved in transplant rejection. These antibodies are produced when the donor’s MICA proteins differ excessively from those of the recipient.

These findings suggest that MICA is a relevant histocompatibility gene to consider when envisaging a transplant, and that testing for anti-MICA antibodies may also be useful in predicting the success or failure of the graft. They must now be validated in large-scale prospective studies in which MICA will be considered in the same way as classic HLA genes.

Following this research, we can now consider the inclusion in routine clinical practice of MICA gene sequencing and the identification of anti-MICA antibodies in patients prior to transplantation to assess histocompatibility with the donor and post-transplant to improve the prevention of rejection. Finally, we also envisage studying the role of MICA in the transplantation of other solid organs, such as the heart, lung and liver,” emphasizes Seiamak Bahram.


[1] Treatments that limit the action of the immune system used in autoimmune diseases and transplants.

[2] University Professor-Hospital Practitioner, Director of Inserm Unit 1109 and LabEx Transplantex, and Head of the Department of Clinical Immunology Laboratory at Strasbourg University Hospitals.

A Gene Therapy Studied in Steinert’s Disease

Steinert’s disease is caused by the abnormal repetitions of a small DNA sequence in the DMPK gene. ©Unsplash

Myotonic dystrophy type 1 (DM1) or Steinert’s disease is a rare and debilitating genetic neuromuscular disease affecting multiple organs and with a fatal outcome. No treatment is available at present. Encouraged by previous research into its molecular causes, researchers from Inserm, CNRS, Sorbonne Université, Lille University Hospital and Université de Lille, in partnership with the Institute of Myology, at the Center for Research in Myology and the Lille Neuroscience & Cognition center, have developed and tested a promising gene therapy that acts directly at the origin of the disease. Initial findings published in Nature Biomedical Engineering show correction of molecular and physiological alterations in mouse skeletal muscle1.

Myotonic dystrophy type 1 (DM1), otherwise known as Steinert’s disease, is a rare, hereditary and genetic neuromuscular condition affecting around 1 in 8,000 people. Debilitating and fatal, it is referred to as a “multisystem” condition because it simultaneously affects the muscles (muscle weakening and atrophy called “dystrophy”; muscle relaxation impairment called “myotonia”) and other organs (cardiorespiratory, digestive and nervous systems, etc.). The expression and course of the disease vary from one patient to the next and no treatment exists as yet.

It is caused by the abnormal repetition of a small DNA sequence (triplet CTG2) in the DMPK (DM1 Protein Kinase) gene located on chromosome 19. In healthy individuals, this sequence is present but repeated between 5 and 37 times. However, in patients with DM1, a mutation occurs whereby the number of triplets increases, producing up to several thousand repetitions.

About the mechanisms enabling gene expression

To obtain the production of a protein, a gene (located in the cell nucleus) is first transcribed into a molecule of RNA. To become a messenger RNA (mRNA), it undergoes maturation, particularly involving splicing. This basically means that the molecule is cut into pieces, some of which are eliminated and others attached. Thanks to this finely regulated process, one gene can lead to the synthesis of different mRNA and therefore of different proteins. After splicing, the mature mRNA will eventually be translated into protein, outside of the cell nucleus.

In Steinert’s disease, the mutated gene is transcribed but the mutant mRNA are retained in the cell nuclei as characteristic aggregates. In the cells of people with DM1, the MBNL1 proteins that normally bind to certain RNA in order to regulate their splicing and maturation are “captured” by the RNA that carry the mutation.

Thus sequestered in the aggregates, it is impossible for them to perform their functions, resulting in the production of proteins that function less well or not at all, some of which have been linked to clinical symptoms.

The team led by CNRS Research Director Denis Furling at the Myology Research Center (Inserm/Sorbonne Université/Institute of Myology) in association with that of Nicolas Sergeant, Inserm Research Director at the Lille Neuroscience & Cognition Centre (Inserm/Université de Lille/Lille University Hospital), focused on a therapeutic strategy to restore the initial activity of MBNL1 in skeletal muscle cells expressing the mutation responsible for Steinert’s disease.

To do this, the scientists engineered modified proteins that present, like the protein MBNL1, binding affinities for the RNA carrying the mutation and as a consequence act as a decoy for these RNA.

When expressing these decoy proteins in vitro in muscle cells from patients with DM1, they observed that they were captured by the mutated RNA instead of the MBNL1 proteins. The latter were then released from the aggregates of mutated RNA and regained their normal function. As a result, the splicing errors initially present in these cells disappeared. Finally, the mutated RNA bound to the decoy proteins proved to be less stable and could be more easily and effectively eliminated by the cell.

Aggregates of mutant DMPK-RNA containing pathological triplet (red) repetitions visualized by FISH-immunofluorescence in the nuclei (blue) of muscle cells (green) isolated from patients with Myotonic dystrophy type1 © Denis Furling and Nicolas Sergeant

The research team then transposed this technique into an animal model in order to verify the validity of this approach in vivo. With the help of viral vectors used in gene therapy, the decoy proteins were expressed in the skeletal muscle of mouse models of Steinert’s disease. In these mice, a single injection was effective, over a long period of time and with few side effects, in correcting the muscle damage associated with the disease, particularly the splicing errors, myopathy and myotonia.

Our findings highlight the efficacy on Steinert’s disease symptoms of a gene therapy based on the bioengineering of RNA-binding decoy proteins with strong affinity for the pathological repetitions present in the mutated RNA, in order to release the MBNL1 proteins and restore their regulatory functions,” declares Furling. However, the authors point out that additional studies are needed before this therapy can be transposed into a clinical study. “This research paves the way for the development of therapeutic solutions in the context of other diseases in which pathological RNA repetitions cause splicing regulation dysfunction,” concludes Sergeant.


1 The striated skeletal muscle is the muscle that is attached to the skeleton by tendons and which, due to its ability to contract, enables the performance of precise movements in a well-defined direction.

2 The coding sequence of a gene consists of the chaining of different combinations of four nucleic acids: adenine, guanine, cytosine, and thymine (replaced by uracil in RNA). These are organized in triplets (or codons) whose correct “reading” by the cell machinery enables the expression of a protein.

Sickle cell disease and transfusion-dependent beta thalassemia: promising results of gene therapy treatment

Globules rouges en forme de faucille (drépanocytose)

Sickle-shaped red blood cells (sickle cell disease) © Inserm/Chevance de Boisfleury, Anne-Marie

Teams from AP-HP, the University of Paris, Inserm, the Imagine Institute, the University of Paris-Est Créteil and the CEA conducted a clinical gene therapy study consisting of transplanting in the patient’s own genetically modified hematopoietic stem cells 1 . This phase I/II clinical trial, promoted by bluebird bio, was carried out in patients with sickle cell disease or transfusion-dependent beta thalassemia, common genetic diseases that affect red blood cells. The results of this work, coordinated by Pr Marina Cavazzana and Pr Philippe Leboulch, were published on January 24, 2022 in Nature Medicine .

As part of the HGB-205 phase I/II clinical trial, four b-thalassemia patients and three sickle cell patients aged 13 to 21 were treated with lentiviral gene therapy. They were followed for a median of 4.5 years after inclusion in the specific dedicated protocols LTF-303 (for b-thalassemia patients) and LFT-307 (for sickle cell patients).

According to the results, the patients with b-thalassemia all became “transfusion independent”, from the first month after the treatment, with a marked improvement in iron overload and a correction of the biological parameters linked to chronic anemia.

A remission of all the clinical symptoms 2 and a correction of the biological parameters sustained over time were obtained in two of the three sickle cell patients treated. A reduction in the transfusion rate was obtained for the third patient with sickle cell disease.

All of these results are maintained over time with more than 4.5 years of follow-up for three patients. No adverse effects linked to the use of the therapeutic lentiviral vector have been observed.

For patients with b-thalassemia, the reported long-term results show that gene therapy by gene addition has become a potentially usable curative option in all patients who do not have a compatible hematopoietic stem cell donor.

In the case of sickle cell disease, the correction of the biological parameters linked to the chronic anemia of two out of three patients provides proof in principle of its effectiveness and opens the way for the introduction of further improvements with the aim of obtaining the same result in all sickle cell patients treated.

Sickle cell disease and transfusion-dependent beta thalassemia

Sickle cell disease and transfusion-dependent b-thalassemia are common genetic diseases. They are therefore a major public health problem. These two chronic anemias are due to mutations in the gene encoding the beta (b) chain of adult hemoglobin (HbA).

Transfusion-dependent b-thalassemia is characterized by an absence (b 0 ) or a marked reduction (b + ) of the synthesis of b-globin chains, responsible for inefficient production of red blood cells and chronic hemolytic anemia and severe, requiring lifelong red blood cell transfusions. The resulting iron accumulation can cause heart failure, cirrhosis, liver cancer and multiple endocrine abnormalities.

Sickle cell disease results from the mutation of an amino acid in position 6 of the b-globin chain (E6V mutation), resulting in the polymerization of sickle cell hemoglobin HbS (hemoglobin “sickle” in English) once the molecules of oxygen (O 2 ) delivered. The polymerization of HbS is at the origin of painful vaso-occlusive crises characterized by a local obstruction of the blood circulation which can affect all the organs and of a chronic haemolytic anemia 3 . Repetition of vaso-occlusive crises and vascular damage affect several vital organs such as the lungs, kidneys, central nervous system and heart, with a significant reduction in the average lifespan of affected subjects.

As with almost all genetic diseases of the hematopoietic system, the only curative option is to transplant hematopoietic stem cells. This approach gives very good clinical results and low mortality when an HLA-compatible sibling donor is available. Unfortunately, a limited percentage of patients can benefit from this treatment (<20%). The use of partially matched donors greatly limits the chances of success and carries significant long-term morbidity, particularly in older patients.

Genetical therapy

Gene therapy, through the transplantation of stem cells from the patient himself, genetically modified, is a promising alternative. It carries low risks of immunological toxicity since no immunosuppressive treatment is required. It can be set up for each patient who needs it, the patient being his own donor.

Gene therapy by gene addition is the first strategy to have emerged in this indication by exploiting the ability of lentiviral vectors 4 to transfer complex genetic information into the genome of hematopoietic stem cells without the cells needing perform cell division.

The lentiviral vector used in this phase I/II clinical trial was developed by the team led by Prof. Philippe Leboulch. This vector allows the synthesis of a modified form of the b-globin chain (b T87Q ), a genetic modification which has a double interest: it gives it an anti-polymerizing property comparable to that of the gamma (g) chain of fetal hemoglobin (HbF) in sickle cell patients and allows its specific dosage in the blood of treated patients. Indeed, the b T87Q -globin chain can be distinguished from other globin chains by high pressure liquid chromatography, in particular from the b-globin chain derived from adult hemoglobins (HbA), produced endogenously in b- patients. thalassemia carriers of mutations b+ and present in transfused red blood cells.


1 Hematopoietic stem cells are nestled in the bone marrow and are at the origin of the different blood cells: red blood cells, white blood cells and platelets.

2 The set of pathological clinical signs that characterize a disease.

3 This is an often hereditary pathology that affects the red blood cells with, ultimately, a pathological reduction in their number incompatible with life and requiring regular blood transfusions, the frequency of which is dictated by the level of Hemoglobin and the clinical symptoms.

4 These are the shuttles of genetic information in the nucleus of cells derived from the HIV-1 virus from which the genetic elements that allow it to replicate and give rise to the infectious disease for which it is responsible have been removed. The elements which enable them to cross the nuclear membrane and to integrate in a stable manner into the genome of the target cells have, on the other hand, been preserved.

Study of gene therapy treatment in Wiskott-Aldrich syndrome


DNA © Fotolia

Teams from the AP-HP, University of Paris, Inserm, within the Imagine Institute, the University College of London, and Généthon, have carried out work on treatment by gene therapy consisting of transplanting the patient’s own genetically modified hematopoietic stem cells as part of a phase I/II clinical trial, promoted by Genethon, in 8 patients with Wiskott-Aldrich syndrome (WAS). The results of this work, carried out in parallel at the Hôpital Necker-Enfants Malades AP-HP, at the Great Ormond Street Hospital and at the Royal Free Hospital in London and coordinated by Pr Marina Cavazzana, Pr Adrian Thrasher and Pr Emma Moris , were published January 24, 2022 in Nature Medicine.

Wiskott-Aldrich syndrome (WAS) is an X-linked complex immune deficiency caused by mutations in the WAS gene which codes for the WAS protein (WASp). This protein is key in the regulation of cytoskeletal actin 1 in hematopoietic cells.

Deficiency of this protein is responsible for small platelet 2 thrombocytopenia and poor function of white blood cells, especially T, B, natural killer and dendritic cells.

The more severe clinical phenotype is characterized by severe infections, bleeding, eczema and manifestations of autoimmunity with a significant risk of developing tumor complications. The severity of clinical expression is related to the level of WAS protein expression. Without curative treatment, patients do not survive beyond the second-third decade of life.

The treatment of choice consists of allogeneic transplantation 3 of HLA-geno-identical hematopoietic stem cells, which has very good results, especially if it is carried out early (<5 years).

The prognosis of the allogeneic transplant actually depends on a number of parameters in addition to the patient’s age, including the degree of HLA compatibility between donor and recipient and the level of hematopoietic uptake.

In the absence of an HLA-compatible donor, the research teams have proposed a treatment by gene therapy which consists of taking blood stem cells carrying the genetic anomaly from patients (CD34+ hematopoietic stem cells), then correct in the laboratory by introducing the healthy WAS gene using a lentiviral vector developed by Anne Galy’s team at Généthon, where the clinical batches of vectors were also produced. The corrected cells are then injected into the patients, previously treated with chemotherapy in order to eliminate the diseased cells and make room for the autologous cells corrected in vitro which will then give rise to the various cells that make up the blood (white and red blood cells, platelets) .

In the article which has just been published in Nature Medicine, the long-term clinical and biological results (median follow-up of 7.6 years) of the phase I/II trial in 8 patients with WAS are described with a special attention paid to two serious complications of this disease: thrombocytopenia and autoimmunity. It should be emphasized that all the patients included in this trial had the more severe form of this immune deficiency and were not eligible for an allogeneic bone marrow transplant.

After gene therapy, the genetically corrected hematopoietic cells showed stabilized engraftment, thus confirming the first results reported in JAMA a few years ago for 6 of them.

The stability of the grafted genetically modified stem cells has made it possible to correct the main symptoms of the disease such as recurrent severe infections or eczema and has made it possible to improve or resolve bleeding and signs of autoimmunity. T cell function was completely restored as demonstrated by the total number of naïve T cells, the restoration of the immunological synapse as well as the functions of these cells which are essential to fight infections.

No adverse effect linked to the use of a retroviral vector has been reported, nor has there been any lack of stability of the graft of genetically modified cells.

Analysis of lentiviral integration sites reveals a polyclonal profile without any clonal expansion or dangerous integration of the vector (risk of neoplastic transformation). Indeed, thanks to lentiviral vectors, the new genetic information is introduced in a stable and random way into the patient’s genome. The ability to sequence the entire genome makes it possible to follow exactly the sites of integration of the new genetic material and to ensure their harmlessness with regard to the physiological functions of the target cell. This sequencing made it possible to validate the long-term safety of these retroviral vectors because no genetic disturbance was observed.

Note: a 30-year-old patient was treated in this trial, thus showing the effectiveness of this treatment in adult patients with a thymus that could be thought to be little or not functional after long years of illness. Similarly, a complete correction of the B lymphocyte compartment was obtained, which made it possible to stop the immunoglobulin substitution in 5 treated patients and to see a significant reduction or even disappearance of the signs of autoimmunity.

All treated patients saw their episodes of spontaneous bleeding decrease significantly in frequency and severity, although for 5 patients the number of platelets remained below normal values.

All in all, gene therapy by gene addition confirms its therapeutic interest for a complex deficit of cellular immunity such as Wiskott Aldrich syndrome. New studies are underway to try to continue to optimize these long-term clinical results. 


1 This is a protein in the cell membrane whose contraction and relaxation activity allows each blood cell to do its job well, such as moving from place to place or eliminating a “diseased” cell. in the case of killer cells.

2 This is the pathological decrease in the number of platelets which, in addition, have a reduced size compared to the physiological value.

3 The term allogeneic refers to cells, tissues or organs taken from a healthy donor to be transplanted into a recipient who is strongly, but not entirely, genetically compatible with the donor.