Huntington’s Disease: Exploring the Avenue of a Potential Neuroprotective Treatment


Huntington’s disease is a rare and hereditary neurodegenerative disorder. A striatal neuron expresses the causative mutant huntingtin protein (red), which accumulates in the nucleus (blue) to form an aggregate of huntingtin and other proteins, including ubiquitin (yellow). © Frédéric Saudou


Huntington’s disease is a hereditary disorder that causes degeneration of the neurons involved in cognitive, motor and psychiatric functions. While existing treatments address the symptoms and relieve certain aspects of the disease, they cannot alter its course. Researchers from Inserm, Université Grenoble Alpes and Grenoble Alpes University Hospital at the Grenoble Institute of Neuroscience are hoping to remedy this. They are studying a new therapeutic approach in the hope of offering patients the first neuroprotective treatment – one that protects neurons – in the years to come. The therapeutic molecule in question has shown promising results in mice and is currently undergoing preclinical evaluation. Their research has been published in Science Advances.

Huntington’s disease is a rare and hereditary neurodegenerative disorder. It usually begins between the ages of 30 and 50 and manifests with cognitive disorders, psychiatric disorders and uncontrolled movements that worsen over time until death some 20 years later. In France, this condition affects around 18,000 people: 6,000 already have symptoms, whereas around 12,000 carry the mutated gene and will develop symptoms later. The team of Frédéric Saudou, Director of the Grenoble Institute of Neuroscience (Inserm/Université Grenoble Alpes/Grenoble Alpes University Hospital), is working on a new therapeutic approach in an attempt to provide solutions for these patients.

The disease is caused by an abnormality on the gene coding for the protein huntingtin, which interacts with and regulates the activity of at least 400 other proteins involved in various cell functions, including the transport of molecules. This abnormality leads to a reduction in the transport of a key molecule, BDNF, in the brain between the cortex and the striatum. The role of this molecule is to promote the survival of neurons and ensure the connections between them. This reduced transport therefore causes the death of neurons in these brain regions.

“Long before symptoms develop, a reduction in BDNF transport is observed. This molecule is essential for the survival of neurons and for neural connections between the cortex and striatum – two regions involved, among other things, in mood and movement control,” explains Saudou, a professor at Université Grenoble Alpes and Grenoble Alpes University Hospital.

The researcher and his colleagues therefore thought that restoring its circulation would at least afford the brain partial protection from neuron death.


A molecule to restore BDNF transport

In collaboration with Inserm Research Director Sandrine Humbert, Saudou and his team had previously shown that BDNF is transported within vesicles made up of numerous proteins, including huntingtin. In this new study, the researchers identified an enzyme that regulates the transport of these BDNF vesicles by controlling a cell mechanism known as “palmitoylation.” By increasing palmitoylation with the help of a molecule called ML348, they were able to restore the transport of BDNF vesicles.

Several in vitro experiments on human neurons and in vivo experiments on mice have shown that ML384 crosses the blood-brain barrier and restores BDNF traffic from the cortex to the striatum. When administered in a mouse model of the disease, it reversed the symptoms.

Injecting ML348 reduced the motor and psychiatric behavioral disorders, allowing the mice to regain activity close to that of their healthy counterparts,” explains Saudou. What is more, this molecule improves BDNF transport in human neurons derived from induced pluripotent stem cells (iPS cells) from Huntington’s patients, demonstrating that this molecule is potentially capable of having an effect in humans.

Following this proof of concept, the researcher and his team will move on to the preclinical testing phase to evaluate, using cell and animal models, the behavior of the molecule in the body, its safety, and identify effective doses. The ultimate goal is to develop a drug for patients. If these results are confirmed, this molecule could become the first “neuroprotective” treatment for Huntington’s disease, sparing certain neurons from degeneration and perhaps slowing its progression.

Discovery of a new variant of SARS-CoV-2 at Henri-Mondor AP-HP hospital


SARS-CoV-2 (yellow) emerging from the surface of cells (blue/pink) grown in the laboratory. Captured and colorized image, Rocky Mountain Laboratories (RML) Hamilton, Montana. © NIAID

Teams from the virology laboratory (Dr Slim FOURATI) and from the “Genomics” platform (Dr Christophe RODRIGUEZ) of the Henri-Mondor AP-HP hospital, Inserm and the University of Paris-Est Créteil (Institut Mondor of Biomedical Research, U955 Inserm-Université Paris-Est Créteil), under the supervision of Professor Jean-Michel PAWLOTSKY, have discovered a new variant of SARS-CoV-2, the virus responsible for COVID-19. The “Henri-Mondor” variant, never described to date, was identified within a cluster made up of three hospital professionals and the spouse of one of them. It is now actively circulating in France.

This discovery was published on March 30, 2021 in the journal Emerging Infectious Diseases , edited by the Centers for Disease Control and Prevention in Atlanta.

The new “Henri-Mondor” variant of SARS-CoV-2 is derived from a viral strain that appeared at the start of the pandemic (clade 19B), which had been replaced by more recent strains during the year 2020.

It is characterized by the presence of 2 deletions and 18 amino acid mutations, of which 7 to 8 are located at key positions of the “spike” protein, involved in the entry of the virus into cells and targets the neutralizing antibodies induced. through natural infection or vaccination. The N501Y and L452R mutations, already observed on other viral variants, seem to improve the interaction of the “spike” protein with its receptor and reduce the action of neutralizing antibodies.

In the four weeks which followed its discovery, the new variant “Henri-Mondor” was found in 29 patients of various geographical origins (Île-de-France, South-East and South-West of France).

Its detection frequency has continued to increase since then with the identification of several clusters and it is more and more frequently found in samples tested by the Henri-Mondor AP-HP hospital platform.

In the Flash 4 survey of March 2, 2021, the “Henri Mondor” variant represented 1.8% of the strains sequenced in France.

New studies will be necessary to know if the “Henri-Mondor” variant is more, as much or less contagious than the other known variants, if it is also detected by the various virological tests, if it is associated with clinical forms. of different severity and / or if its sensitivity to the action of antiviral treatments and to vaccine protection is impaired by the presence of its numerous mutations.

The discovery of a new variant of SARS-CoV-2, which is actively circulating in several French regions, underlines the need for systematic monitoring of the evolution of viral variants, associated with a reactive alert system.

The Henri-Mondor AP-HP hospital platform is one of the 4 platforms labeled by the Ministry of Health and Solidarity for molecular surveillance of the SARS-CoV-2 virus, as part of the EMERGEN national surveillance project coordinated by Public Health France and the ANRS Emerging Infectious Diseases. This platform offers a production capacity of more than 1,000 sequences per week, dedicated to epidemiological surveillance, and will soon be able to double this activity for the performance of specific studies. 

COVID-19: A New Serological Test to Improve Monitoring of the Pandemic

Cellules infectées par le SARS-CoV-2

SARS-CoV-2 infected cells. © Sébastien Eymieux and Philippe Roingeard, Inserm – Université de Tours

A new test to detect antibodies to SARS-CoV-2 that is reliable, inexpensive and needs no special equipment? This is the proposal of an international scientific team, of which one of the members is an Inserm researcher at the Institute of Pharmacology and Structural Biology (CNRS/Université Toulouse III – Paul Sabatier). Developed in collaboration with the University of Oxford, this serological test is based on a single reagent that causes red blood cells to agglutinate in the presence of antibodies specific to SARS-CoV-2. Potential initial applications for this test include clinical and epidemiological research. The original article describing the research was published in Nature Communications on March 29, 2021.

Detecting antibodies to SARS-CoV-2 is epidemiologically essential when it comes to monitoring the progression of the epidemic. It is also necessary for scientists studying the links between past contact with the virus and protection against renewed infection. 

Several tests are already available and while effective, they require sophisticated and costly equipment that limits their widespread use, particularly in countries with more limited resources.

That is why Etienne Joly, an Inserm researcher at the Institute of Pharmacology and Structural Biology (CNRS/Université Toulouse III – Paul Sabatier) has devised a new test that is easy to perform and inexpensive. Developed in collaboration with Alain Townsend at the University of Oxford in the UK, the test is based on hemagglutination – a method that has been known for over 50 years and is commonly used to determine blood groups.

The process is based on the agglomeration, visible to the naked eye, of red blood cells in the presence of specific antibodies – in this case directed against SARS-CoV-2. The secret of its simplicity lies in the use of a single reagent consisting of a recombinant protein that associates an antibody recognizing a red-blood-cell surface molecule (glycophorin) with the RBD peptide of the SARS-CoV-2 Spike protein (the domain recognized by the neutralizing antibodies against the virus). When brought into contact with blood, this reagent binds to the red blood cells.

test sérologique Covid-19

The test requires two V-bottomed wells, in which 2 microliters of the blood to be tested are diluted. The left-hand wells – the negative controls – contain the dilution medium, whereas those on the right contain the dilution medium plus the IH4-RBD reagent. After one hour of incubation, the red blood cells have settled, forming a red “button” at the bottom of each well. The plate is then tilted at an 80° angle for 30 seconds and the non-hemagglutinated red blood cells form a teardrop – as can be seen in the left-hand wells. The presence of antibodies in the sample tested on the second line is revealed by the red blood cells agglutinated by the reagent that remain as a “button” at the bottom of the well. © Etienne Joly


If, in this same blood sample, antibodies to SARS-CoV-2 are present, they recognize the RBD fragment of the reagent present on the surface of the red blood cells. These antibodies can bind simultaneously to RBD fragments that may be on two different red blood cells, thereby linking the latter together and creating a cluster. Such agglomeration reveals recent or past infection. 

No sophisticated techniques are required for these procedures. The blood can be collected by means of a simple finger-prick, like people with diabetes do when testing their blood sugar levels every day.

Furthermore, the reagent is supplied in lyophilized form that requires no refrigeration and the result can be read with the naked eye. An additional advantage is that this reagent is easy and inexpensive to produce. Its estimated cost of 3 euros per 1000 tests makes it affordable for countries with fewer resources. 

90% sensitivity

The test was evaluated on over 400 serum samples from patients treated in various UK hospitals and presented 90% sensitivity. This means that the test will only detect antibodies in 90 out of every 100 people who possess them. A percentage that Joly is currently working on increasing because it is slightly lower than that of the ELISA tests commonly used in diagnostic laboratories (although it is already better than that of the COVID rapid diagnostic orientation tests available in pharmacies for around ten euros). In terms of specificity, the test achieves 99% – meaning that out of every 100 people who do not possess antibodies, the test will return a false positive for just one of them.

The scientists are now making this test available to interested research laboratories in order to help them elucidate the dynamics of the COVID-19 epidemic. Another advantage is that this test should be easily adaptable to other diseases.

“By modifying the protein of the reagent, it will be possible to tackle the screening of antibodies directed against the variant forms of the virus, or other pathogens such as HIV or the tuberculosis bacterium. We just have to choose the viral or bacterial protein predominantly targeted by antibodies,” concludes Joly.

Air Pollution: Black Carbon Linked to Increased Cancer Risk

Pollution de l'air

Air pollution is linked to thousands of deaths each year in France. © Adobe Stock

Air pollution is responsible for thousands of deaths each year in France. Knowing more about the health effects of its various components is therefore a priority. Scientists from Inserm, Université de Rennes 1 and EHESP School of Public Health at Irset and their counterparts from Université Versailles Saint-Quentin-en-Yvelines (UVSQ) at Joint Service Unit 11 chose to focus on black carbon – a constituent of the fine particles produced by incomplete combustion, particularly related to automobile traffic. While it has already been associated with numerous health problems, this research suggests for the first time that long-term exposure to black carbon is also linked to an increased risk of cancer, particularly of the lungs.Their findings were published in EHP on March 24, 2021.

Pollution of the air by fine particles1 is a major public health concern, with the scientific literature from the past several years showing a link to the risk of cancer. In 2013, the International Agency for Research on Cancer (IARC) actually categorized all fine particles as known human carcinogens.

However, the term fine particles represents a “black box”: not all of the components of these particles are likely to impact cancer risk in the same way. Several candidates are being studied to explain their adverse health effects. One such candidate is black carbon, named for its composition and color – a component of the fine particles resulting from incomplete combustion whose generally harmful effect on health has already been pointed out by the World Health Organization (WHO).

In their work at Irset (Inserm/Université de Rennes 1/EHESP) and Joint Service Unit (JSU) 11 (Inserm/UVSQ), Inserm researchers Emeline Lequy and Bénédicte Jacquemin specifically evaluated the link between long-term exposure to black carbon and lung cancer in order to elucidate the role of this component in the adverse health effects of air pollution.


Residential history and exposure to pollution

The scientists used health data from the participants in the Gazel cohort, which was set up by Inserm within JSU 11 in 1989 and groups around 20,000 participants who are followed up every year.2 The strong point of this cohort is that the history of where all the participants have lived over the past 30 years is available. Thanks to the European project ELAPSE, the researchers also had access to very precise estimates of the levels of pollution relating to where each participant had lived.

This cohort is also very well described when it comes to risk factors for cancer, such as the participants’ smoking habits, alcohol consumption, and occupational exposures.

Based on these data, the researchers and their colleagues determined the degree of association between the levels of local pollution to which the participants have been subject since 1989 and the risk of developing cancer in general, or lung cancer more specifically.

Using statistical models adjusted to take into account other risk factors and isolate the concomitant effect of the fine particles that include black carbon, they were able to specifically show the link between black carbon and cancer risk.

Their study suggests that the higher the levels of exposure to black carbon in the participants’ localities, the higher the risk of lung cancer. Those with the highest levels of exposure to black carbon since 1989 presented an approximately 20% increased cancer risk compared to those with the lowest exposures. An increased risk that rose to 30% for lung cancer. This component could therefore partially explain the carcinogenic effects of air pollution.

These findings, which are unprecedented on cancer incidence and which reinforce the existing scientific literature on other health problems, are important when it comes to guiding public decision-making in terms of health policies and the regulation of air pollution.

“At an individual level, it is difficult to recommend measures for limiting exposure to black carbon from ambient air particles. However, it is possible to adjust public policies if we can show which air pollutants cause the most harm. So we hope that our findings will help to expand knowledge in order to guide and refine these policies, for example by taking specific measures against black carbon, which mainly comes from automobile traffic,” emphasizes Jacquemin, the study’s last author.

The team now wishes to continue its analyses in order to study the effects on health of other specific pollutants, such as metals. The objective is also to continue to study the impact of black carbon in other, larger, cohorts such as Constances, with participants who have been recruited more recently, to determine whether air pollution, even at low levels, can affect health.


1 Particles with a diameter of less than 2.5µg, or PM 2.5. The term encompasses particles of natural and human origin.

2 The Gazel cohort was set up in 1989 by Inserm, in cooperation with several departments of EDF-GDF (French national gas and electricity companies). Since 2018, the collection of information from Gazel volunteers has been harmonized with that of the Constances cohort.

Mental Health Deterioration in Lockdown: Results of a Mavie Cohort Study

Dépression Confinement

Levels of anxiety, depression and perceived mental health deteriorated significantly during the lockdown. © Erik Mclean on Unsplash

Calyxis in Niort and the Inserm-Université de Bordeaux Population Health Research Center have published the findings of their study on the mental health impacts of lockdown in the journal Globalization and Health. Anxiety, depression, and self-rated mental health saw marked deteriorations in the MAVIE cohort, particularly in women, young people, elderly people, and those with less than 30 m2 of living space.

In 2014, Inserm and Université de Bordeaux had joined forces with the Calyxis risk prevention expertise center to set up the MAVIE Observatory intended to study everyday-life accidents among 10,000 volunteers in France. During their recruitment, they were asked to complete various online questionnaires intended to find out about their health and lifestyles. Over the 6 years that followed, any everyday-life accidents that occurred were recorded. At the time of the first COVID-19 lockdown, given that the mental health status of the MAVIE volunteers had been measured at the recruitment stage, a second estimate of this status was carried out in order to compare it to the first.

Two validated scales were used: the Patient Health Questionnaire-9 (PHQ-9) to measure depression symptoms and the Generalized Anxiety Disorder 7-item Scale (GAD-7) to measure anxiety symptoms. A third indicator was introduced, in which the participants were asked to rate their mental health on a scale from 1 to 10.

A total of 1237 volunteers agreed to participate in this study by completing this second questionnaire. Based on their responses, the researchers found that the proportion of volunteers with anxiety symptoms had increased from 17% to 20%. However, the proportion of those with depression symptoms had changed only slightly – from 27% to 28%. The self-rated mental health score had decreased from 7.77 to 7.58 – albeit to a lesser extent for those used to spending more than an hour a day on a screen, perhaps because it is an activity compatible with lockdown.

Those having presented more depression symptoms during lockdown were women, young people, elderly people, and those with less than 30 m2 of living space.

Those with poor physical health had a threefold greater risk of presenting more symptoms of anxiety during confinement.

The same study was repeated during the second French lockdown and the data are currently being analyzed. Initial results show a marked deterioration in these same three mental health indicators.

COVIREIVAC Platform: COVID-19 Vaccine Research Continues with the Launch of New Projects


New projects being launched within the framework of COVIREIVAC. © Adobe Stock


Launched in October last year, the purpose of the COVIREIVAC platform coordinated by Inserm and F-CRIN in conjunction with 32 university hospitals and a network of 11 immunology laboratories is to conduct and promote first-class clinical vaccination research in France. Since then, some 50,000 volunteers have signed up to participate in that research and improve knowledge of these new vaccines, making this is an unprecedented initiative in our country. COVIREIVAC is steered by Inserm and the clinical operational aspects of the various university hospitals are coordinated by the Paris Hospital Group AP-HP. In addition to France’s participation in the clinical trial evaluating the efficacy of two doses of Janssen’s vaccine candidate (already licensed for use with one dose), which began in February, other ambitious projects are being launched within the framework of COVIREIVAC.

Although several COVID-19 vaccines are now available, it is imperative to continue research in order to deepen scientific knowledge, particularly in terms of the duration of protection afforded by the vaccines and the quality of immune response – including in those whose health conditions affect their immunity.

The objective of the clinical trials coordinated by COVIREIVAC is to provide answers to these research questions. The CoviCompare trials and the COV-POPART cohort are expected to contribute data that will be important to the vaccine strategy.

The objective of the CoviCompare trials is to study the immunogenicity of different COVID-19 vaccines, i.e. the immune responses they induce, particularly in those aged 65 and over compared with younger adult populations.

This research is expected to provide a better understanding of how the available COVID-19 vaccines work and will guide their use to achieve optimal efficacy in the different population types. The participants, all of whom are vaccinated (there is no control arm), will be followed up for a period of two years. The results will be analyzed and compared between age groups in order to test immune response intensity and duration and provide information for use in deciding, if applicable, whether or not boosters will be needed according to age and/or immune status.


AP-HP-CoviCompare-m: refining knowledge of the immune responses of people aged 65 and over vaccinated with Moderna

Moderna’s COVID-19 vaccine is based on messenger RNA technology. Already tested on more than 30,000 people in the USA, this vaccine has proven to be 94.1% effective in the general population and 86.4% effective in people over 65. It is now being used in France.

Sponsored by the Paris Hospital Group AP-HP, this trial began on February 12 of this year and is ongoing in six French centers: Créteil (Henri-Mondor Hospital AP-HP), Lille, Lyon, Marseille, Paris (Cochin Hospital AP-HP), and Saint-Étienne.

In concrete terms, the trial envisages the creation of three groups of 60 participants:

  • The first whose participants are between 18 and 45 years of age
  • The second whose participants are between 65 and 74 years of age
  • And the third whose participants are aged 75 and over

The volunteers will each receive two injections of the vaccine, 28 days apart.


ANRS0002S CoviCompare-P: refining knowledge of the immune responses of people aged 65 and over and COVID-19-experienced individuals vaccinated with Pfizer/BioNTech

The messenger RNA vaccine developed by Pfizer/BioNTech – the first to be validated in Europe – has shown 95% efficacy after two doses, following testing in over 44,000 people. The French National Authority for Health (HAS) has recently published an opinion (only available in French) recommending a single vaccine dose for people having previously contracted COVID-19.

Sponsored by ANRS | Emerging Infectious Diseases, the autonomous agency within Inserm tasked with coordinating COVID-19 research, this trial began on March 8 of this year. It is taking place in 11 centers: Créteil, Nantes, Caen, Clermont-Ferrand, Lyon, Nîmes, Brest, Tours, Strasbourg, and Paris (Saint Louis and Cochin).

The objective is to evaluate in detail the immune responses induced by the Pfizer/BioNTech vaccine in people aged 65 and over, and to compare those of people having already contracted COVID-19 with those of people who have never had it.

The participants will be assigned to the same age groups as for CoviCompare-m in addition to three other categories (150 people who have never contracted COVID will receive two vaccine doses and 150 participants having already had COVID will receive one).


ANRS0001S COV-POPART: a vaccine cohort to evaluate immune responses to COVID-19 vaccines in specific populations

COV-POPART (the COVID-19 special populations vaccine cohort), sponsored by ANRS | Emerging Infectious Diseases, is a national cohort that will include a total of 10,500 participants across 35 centers, and has been labelled a national priority by France’s interministerial research working group.

The project has been constructed with over 10 national and international learned societies and seven patient associations (France Rein – Transhépate – ARSEP – CNAO – FFD – EGMOS – TRT5 CHV*), which will also play an active role in recruiting and following up participants.

The objective of the cohort is to evaluate the production of antibodies against COVID-19 in 8,650 vaccine recipients with diseases that might affect their immunity: HIV-1, diabetes (types 1 and 2), obesity, autoimmune and systemic autoinflammatory diseases (vasculitis, lupus, etc.), chronic inflammatory rheumatism, multiple sclerosis (or inflammation of the optic nerve), cancer (even without treatment for the previous 2 years), allotransplant recipients, solid organ transplant recipients (lung, liver, kidney, heart, pancreas), chronic renal failure (stages 4 and 5), and hypogammaglobulinemia (low immunoglobulin levels in the blood).

In order to compare their immune responses, a control group of 1,850 vaccinated individuals without these diseases was also recruited.

The cohort should also make it possible to identify potential vaccine failures and study the role of the variants in those failures. Participants will be followed for a period of two years after the last injection of the vaccine, with the help of the COVIREIVAC centers and 4 additional centers mobilized for this project. This cohort will provide essential data for vaccine policy in these vulnerable populations that are at particular risk of developing severe forms of COVID-19.


*France Rein – Transhépate – ARSEP French foundation to aid multiple sclerosis research – CNAO French collective of associations for people with obesity – FFD French federation of diabetics – EGMOS French association for bone marrow transplant recipients – TRT5 CHV French collective of associations against HIV, hepatitis and STIs.

Certains cocktails de pesticides favoriseraient le risque de cancer du sein chez les femmes ménopausées

Charcot-Marie Tooth disease: A 100% French RNA-based therapeutic innovation

Maladie de Charcot

© Liliane Massade, Diseases and hormones of the nervous system (INSERM/Université Paris-Saclay)

  • Charcot-Marie Tooth disease causes progressive paralysis of the legs and hands. No treatment is available today.
  • After more than a decade of research, a French team has developed an RNA-based therapy that allows model mice to regain their mobility.

Charcot-Marie Tooth disease is the most common hereditary neurological disease in the world. It affects the peripheral nerves and causes progressive paralysis of the legs and hands. No treatment is currently available to fight this disease, which is due to the overexpression of a specific protein. Scientists from the CNRS, INSERM, the AP-HP and the Paris-Saclay and Paris universities have developed a therapy based on degrading the coding RNA for this protein in mice. Their work is patented and was published on 9 March 2021 in Communications Biology.

In molecular biology, transcription is when a DNA molecule is copied to make an RNA molecule. This RNA molecule is then “translated” into a protein, which can perform different functions within the body’s cells. When a specific protein called PMP22 is made twice as much as normal, it causes type 1A of genetic Charcot-Marie Tooth disease to develop. This overproduction leads to gradual paralysis of the legs and hands.

The challenge then, is to standardize the expression of this protein in people with Charcot-Marie Tooth disease. French scientists1 have developed a patented2therapy based on reducing RNA coding for the PMP22 protein. To achieve this they used other small RNA molecules capable of interfering with a specific RNA, here the one that encodes PMP22, and of degrading or reducing its translation into protein.

The difficulty in developing this therapy has been to stabilise these small RNAs, known as small interfering RNA or siRNA, which degrade very rapidly in biological environments.

Researchers have coupled them with another molecule called squalene, which is typically used in cosmetology and pharmacology. Biocompatible, biodegradable and forming nanoparticles in water, squalene protects siRNA from degradation. It also controls the size of the particles formed and the amount of siRNA injected.

These scientists then showed, in mice models for this disease, that injecting these interfering RNAs completely and rapidly restored of mouse locomotor activity and strength. The siRNAs penetrate the peripheral nerves, strengthen the myelin sheath3 around those nerves, and normalize the nerve signal velocity. The effect of treatment lasts for three weeks for severe forms and more than ten weeks for milder forms of the disease.

This therapeutic strategy for hereditary peripheral neuropathies, developed entirely in France, is proof of concept for a new precision medicine based on siRNA normalization of the expression of an overexpressed gene. It will now be developed in humans with pre-clinical and clinical studies.


1 At the Laboratoire Maladies et Hormones du Système Nerveux (INSERM/Université Paris-Saclay), the Laboratoire Aspects Métaboliques et Systémiques de l’Oncogénèse pour de Nouvelles Approches Thérapeutiques (CNRS/Université Paris-Saclay/Institut Gustave Roussy), the Institut Galien Paris-Saclay (CNRS/Université Paris-Saclay), the Service de Neurologie – Centre de Référence Neuropathies Périphériques Rares at the CHU de Limoges, the Service de Neurologie – Centre de Référence National des Neuropathies Amyloïdes Familiales et Autres Neuropathies Périphériques Rares at the CHU du Kremlin-Bicêtre (AP-HP/Université Paris-Saclay) and the Environmental, Toxicity, Therapeutic targets, Cellular Signaling and Biomarkers Laboratory (INSERM/Université de Paris). This work has received ANR funding under the Avenir programme (Labex NanoSaclay, reference ANR-10-LAM-0035).

2 References: WO/2020/064749, PCT/EP2019/075736

3 Myelin is a lipid-rich layer that isolates axons from neurons and allows for increased transmission of the nerve signal. Myelin dysfunction leads to very disabling nerve diseases. The PMP22 protein is present in myelin and is essential for nerve function.

COVID-19: Timing Issues Prevent SARS-CoV-2 Host Cells From Stopping Replication

Cellules infectées par le SARS-CoV-2

SARS-CoV-2 infected cells (in green). The size scale corresponds to 10 µm. © Joe McKellar

Although the SARS-CoV-2 target cells in the respiratory tract produce antiviral molecules following infection, it is too late to prevent the virus from replicating. This is the conclusion drawn by researchers from Inserm, CNRS and Université de Montpellier at the Infectious Disease Research Institute of Montpellier. Their findings have been published in the Journal of Virology

Inserm researcher Caroline Goujon and her team have spent a long time studying viruses at the Infectious Disease Research Institute of Montpellier (CNRS/Université de Montpellier). When the COVID-19 epidemic emerged, Goujon and her colleague Olivier Moncorgé decided to focus on the novel coronavirus, initiating several projects – one of which fundamental, in an aim to understand how the target cells respond when infection strikes.

At a time when the scientific community still had questions about SARS-CoV-2, building knowledge on the early stages of infection to understand how the virus enters the body and how it can be blocked was essential.


In search of interferons

In their recent study, the scientists describe this response by the target cells in the respiratory epithelium. They began by exposing respiratory epithelial cells to the virus, analyzing its multiplication in the hours that followed. In parallel, they looked for the presence of interferons, which are antiviral molecules naturally produced by the cells in the event of infection.

What they found was a rapid increase in viral load after 48 hours and the high production of two types of interferons (type I and type III) 48 to 72 hours after infection. The production of these molecules is generally triggered by certain host cell proteins – known as sentinel proteins because their task is to detect the presence of viruses.

The researchers then used the CRISPR-Cas9 technique to delete the genes coding for the main sentinel proteins and found that the absence of one of the genes, MDA- 5, prevented the production of the interferons. However, this phenomenon had no impact on the replication of the virus. “With or without the production of these interferons, which are supposed to counteract the virus, replication took place in the same way in our epithelial cell model,” clarifies Goujon.

However, research by the team and many other groups shows that placing the target cells in contact with these same interferons in the hours preceding infection considerably reduces the ability of the virus to replicate, dividing the replication rate by at least ten.

“Therefore the antiviral activity of interferons is not to be called into question when it comes to SARS-CoV-2. Their inefficacy in our model is due to a problem of timing. Their release occurs too late to block viral replication,” she explains. In order to have a protective role and avoid viral replication, it appears important for their production to take place earlier.


Open up avenues of therapeutic research

This research also opens up new prospects when it comes to the severe forms of COVID. “We know from previous studies that natural interferon levels are low in patients with severe forms of COVID-19 compared to those with less severe forms. Stimulating the body’s production of interferons early on by activating the MDA-5 pathway could limit the risk of developing severe forms in some patients,” she adds.

Some research teams have already begun to study the early administration of interferons in a number of clinical trials. As for Goujon and her colleagues, they have already made a start on the next phase of the project: identify the genes in the target cells whose expression is stimulated by infection and which help to slow viral replication – thereby possibly opening up new therapeutic avenues.