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Month: June 2018

A new twist on how parasites invade host cells

Posted on by Priscille Rivière

Crédits: Inserm/Bougdour, Alexandre

Researchers from CNRS, INSERM and the Université Grenoble Alpes have decoded the mechanisms used by the parasite Toxoplasma gondii to enter the cells of a host. Using high-resolution, high-speed imaging, they identified a unique process by which the parasite closes the ‘entry door’ it creates in order to enter and inhabit a host cell. The results of the study, at the crossroads between cell biology, parasitology and biophysics, appear in the 28 June 2018 edition of Cell Host & Microbes.

Toxoplasmosis is a widespread infection caused by the parasite Toxoplasma gondii, which multiplies within a host and irreversible tissue damage. Humans primarily become infected by eating undercooked meat and poorly washed fruits and vegetables. After infecting the digestive system, the parasite enters deep tissue in the nervous system, among other places, and remains there to develop, nearly undetected.

To do so, T. gondii implements an ingenious invasive strategy. Scientists at the Institute for Advanced Biosciences (IAB) (CNRS/INSERM/Université Grenoble Alpes) have successfully reconstructed the steps taken by the parasite to gain entry to a host cell. T. gondii injects a protein complex into the host cell membrane to form a door through which it passes in a matter of seconds. It then performs a twisting motion to close the door behind itself. This rotational force also allows it to seal itself into a vacuole, a small sac that acts as a nest, where it continues to develop at the host’s expense.

The study, pioneering in its field, unveils a stage in the invasion process that likely constitutes one of the first “signals” to Toxoplasma gondii that it can begin the intracellular phase of its cycle. The team is now focusing on understanding in detail the mechanical properties of this door that opens and closes cell membranes.

Copyright: © Isabelle Tardieux

Once it enters the cell, the parasite rotates to close the door it has opened. This movement also seals it into a vacuole, a sac where it stays and develops.

A Summer of Science and Art with the Participation of Inserm

Posted on by Priscille Rivière

©Amelie Blanc, Robin Lopvet, Alexandre Kong A Siou

Inserm has long played a proactive role in scientific outreach in order to share science and biomedical research advances with the general public. And this summer 2018 will be no exception, with its host of events in which art and science will meet, in which our researchers will participate in La recherche de l’art #7 in Arles, Binôme in Avignon, and the Science in The City festival in Toulouse. The diary of Inserm’s scientific and cultural events, which include a photography exhibition, play, and visual performances, is presented below.

 

Inserm and National Photography School ENSP present La recherche de l’art #7

Since 2011, Inserm laboratories offer photographic residencies to young ENSP graduates. La recherche de l’art brings art and science together to offer a vision that is astonishing, unexpected and always innovative. Philippe Rostagno, Researcher at the Mediterranean Center for Molecular Medicine (Nice) hosted Alexandre Kong A Siou; Sophie Nunes Figueirado from the Brain and Spine Institute (Paris) hosted Robin Lopvet; Laurence Doumenc from the Digestive Health Research Institute (Toulouse) hosted Amélie Blanc.

Save the date: The private viewing, to take place in Arles on July 3 at 4:30 p.m. in the presence of the photographers and Inserm researchers is where lens and laboratory meet. A dedicated publication has been produced. Galerie du Haut – Ensp, 16 rue des Arènes, Arles, from July 2 – August 26.

 

Inserm and theater company les sens des mots present the new edition of binôme at the Avignon Festival

A singular encounter between an Inserm researcher and an author has given us this play, which is interpreted by three actors. The reading, by les sens des mots, will be accompanied by an original musical creation. The result – sensitive, astonishing and often funny – gives us a different look at science and those involved in it.

Save the date: Bobby et le garçon X-Fragile, to be held on July 20 at 5:30 p.m. in the Cour Minérale of Université d’Avignon, is written by Sonia Ristic, inspired by her encounter with Inserm Neurogenetics Research Director Barbara Bardoni.

 

Inserm present at Science in the City, a general-public science festival as part of ESOF 2018 in Toulouse

  • The Inserm Occitanie Pyrénées Regional Office is a partner of the La science en taille XX elles project driven by the Femmes&Sciences association and CNRS Midi-Pyrénées whose aim is to promote female scientists, deconstruct stereotypes and inspire young women to pursue scientific careers. Twelve portraits of female scientists, including Inserm Research Director Emmanuelle Rial-Sebbag, will be exhibited from July 6 – 15 in the windows of Galeries Lafayette and in partnership with the Toulouse tourist office, celebrating female scientists who, despite having marked history, are forgotten or unknown. Meetings with scientists from July 7 – 9 at the Espace des diversités et laïcités with a showing of Inserm films “Gender and health: beware of clichés!”.
Save the date: from July 6 – 15, 2018.

 

  • hEARt, a musical journey in the imaginary world of the heart created by composer Christophe Ruetsch, supported by Inserm with the participation of Franck Lezoualc’h, Inserm Research Director at the Institute of Cardiovascular and Metabolic Diseases.
Save the date: from July 10 – 15 at Chapelle des Carmélites, entry free from 10 a.m. – 6 p.m.

 

Links:

La recherche de l’art #7

La recherche de l’art on the Inserm website

Binôme edition #9

Binôme on the Inserm website

Binôme teaser on the Inserm YouTube channel

Science in the city

La science en taille XX – Elles on the Inserm Occitanie Pyrénées website

The inauguration of hEART on the Inserm Occitanie Pyrénées website

Hypertension: An international study shows the blood pressure benefit of endovascular renal denervation focused ultrasound in patients receiving no antihypertensive drug

Posted on by Priscille Rivière

After reporting the first positive results of renal denervation in blood pressure (HBP) resistant in the journal The Lancetin 2015, the team of the Center of Excellence in Hypertension and CIC1418 APHP-INSERM led by Dr. Michel Azizi and that of the interventional radiology department led by Prof. Marc Sapoval from European Georges Pompidou Hospital, AP-HP , obtained promising new results in hypertensive patients receiving no antihypertensive therapy as part of an international study. They provide, for the first time, evidence of the reduction in blood pressure after renal denervation focused ultrasound in this indication. The findings of the RADIANCE-SOLO study, coordinated by the European Hospital Georges Pompidou, AP-HP, were presented at EuroPCR in Paris and at the Congress of the European Society of Hypertension in Barcelona. They are published in the journal The Lancet . This opens new perspectives for treatment in this disease that affects 30% of the French population to consider in the future an alternative to drug therapy for some patients.

Renal denervation endovascular consists in interrupting the electrical activity of the nerves of the sympathetic nervous system in kidney for delivering focused ultrasound through a catheter into the RADIANCE-SOLO study or by using another technology based on an electric current of low intensity. This new therapeutic approach was originally developed to treat severe hypertension resistant to at least 3 antihypertensive drugs.

An international study led by Professor Michel Azizi of the European Hospital Georges Pompidou, AP-HP – Department Head, Center of Excellence in Hypertension and Coordinator CIC1418 APHP-Inserm – and the University Paris-Descartes and Dr. Laura Mauri (Harvard University, Brigham and Women’s Hospital, Boston, USA) was conducted in collaboration with a US start-up. It was designed to objectively assess the blood pressure efficacy and safety of renal denervation ultrasound against a fictitious speech – called “sham” – for the first time in patients receiving no medication for their hypertension.

A total of 146 patients with moderate hypertension taking no antihypertensive drug were distributed by drawing lots among the group treated with renal denervation or group “sham” limited to a diagnostic arteriography. 

Neither the patients nor the medical team that tracks patients knew which group they were assigned by lottery. The fictional or “sham” surgery with keeping the knowledge of the randomization of patients and medical teams eliminates the placebo effect especially in hypertension and has been approved by health authorities and the protection committee of people in France and worldwide.

After 2 months follow up without addition of antihypertensive treatment except in cases of necessity of safety, study results show that:

  • daytime ambulatory systolic pressure was reduced significantly greater extent in the denervation group (-8.5 mmHg) than in the sham group (-2.2 mmHg), a difference of 6.3 mmHg in favor of denervation kidney. 
  • over 66% of patients treated with renal denervation had a reduction of 5 mmHg or more daytime ambulatory systolic blood pressure, compared to 33% in the control group.
  • 20% of patients treated with renal denervation had normalized their blood pressure without taking any antihypertensive medication against 3% in the control group.
  • No serious adverse events were observed.

(* MmHg: millimeters of mercury)

Renal denervation is therefore a medium-term hypotensive effect in patients with hypertension and receiving no antihypertensive drug.

In France, high blood pressure affects about 30% of the population and can lead to serious cardiovascular or renal complications, sometimes fatal. Despite the availability of many different drug classes, hypertension remains uncontrolled in more than 45% of hypertensive patients in France [1] and in the world.

“The long-term maintenance of the reduction in blood pressure after renal denervation procedure would have beneficial consequences in terms of reducing cardiovascular and cerebrovascular events in patients with hypertension. Monitoring at 6, 12 and 36 months is in progress and provide guidance on keeping away from the blood pressure reduction, “   says Dr. Michel Azizi, Georges Pompidou European Hospital, AP-HP. 

The RADIANCE-HTN research program is ongoing to include patients with resistant hypertension is at higher risk of complications. Pioneers patients and the medical community to seek together new perspectives for simplifying and customizing the treatment of hypertension in France and around the world to contribute to its better control and reduce complications.

[1] epidemiological study conducted by Public Health ESTEBAN France and worldwide study Measurement Month May 2017

How does air pollution affect the placenta ?

Posted on by Priscille Rivière

Crédits: AdobeStock

Researchers from Inserm, CNRS and Université Grenoble Alpes working at the Institute for Advanced Biosciences (Joint Research Unit 1209) have analyzed the consequences of environmental exposure in utero using data collected from a cohort of 668 women. Exposure to atmospheric pollution is associated with epigenetic modifications in the placenta, presenting a risk to the fetus. These findings were published in Environment International on June 21, 2018.

Exposure to air pollution during pregnancy presents a risk to the health of the fetus and child. According to a number of studies, exposure to air pollution is linked to harmful effects, such as preeclampsia (hypertension associated with the presence of protein in the urine) in the pregnant woman, as well as reduced birth weight and possibly also lung function deterioration and neurodevelopmental disorders in the child. The mechanisms that explain the effect of air pollutants on the development of the fetus and child could involve impairment of the placenta.

The researchers conducted a study based on 668 mothers and their children in the EDEN cohort. The pregnant women were recruited between 2003 and 2006 in the university hospitals of Nancy and Poitiers. The scientists observed that the mothers most exposed to nitrogen dioxide (gas produced by automobile, industrial and thermal combustion processes) during their pregnancies presented an epigenetic modification on the ADORA2B gene. “Defects in the expression of this gene have in other studies been associated with preeclampsia, a commonly-occurring condition in pregnancy which can be serious if it is not managed,” explains Inserm researcher, Johanna Lepeuler. The average exposure levels in the population studied were below the annual limit set by the European Union air quality directive (40 mg/m3 for nitrogen dioxide).

The results of this study thereby confirm part of the hypothesis according to which prenatal exposures to air pollutants, at levels commonly found in Europe and France, could be harmful to the health of the pregnant woman and unborn child.

It is the first study on air pollutants to focus on the issue based on an analysis of large-scale epigenetic data (concerning more than 400,000 epigenetic locations). Previous studies focused on specific genes.

This research project was funded by the Fondation de France and various public institutions.

Research into a Ricin Antidote – What’s New?

Posted on by Priscille Rivière

Crédits: AdobeStock

Back in 2016, a team from Inserm had made a major contribution to the development of an aerosol capable of rapidly administering, into the deepest reaches of the lungs, an antidote to ricin. Ricin is highly toxic when inhaled and dreaded in the event of a bioterrorism attack.

Three years: this is the time it took an Inserm team at the Research Center for Respiratory Diseases (Tours) to develop an aerosol capable of depositing a ricin antidote into the deepest reaches of the lungs. This research was performed as part of an international consortium, involving the Université de Tours, the French Armed Forces Biomedical Research Institute (IRBA) and DTF medical (Saint-Etienne), a company specialized in innovative medical devices.

Among the challenges addressed: adapt this antibody for clinical use and, above all, succeed in effectively delivering it into the lungs – particularly into the small air sacs where ricin has a devastating effect.  This is the reason why the French army sought the help of an Inserm laboratory specialized in biological medicinal product administration via the respiratory route.  The project was funded by the French government defense procurement and technology agency (DGA).

Consult the full article on the Inserm website

Five years after a cancer diagnosis, quality of life and employment status remain strongly impacted

Posted on by Priscille Rivière

Adobestock

Over 3 million people in France are currently living with cancer or have recovered from it.
While the number of new cases diagnosed each year continues to increase, the advances made in diagnosis and treatment have made it possible to push back mortality.  The disease remains a difficult ordeal for those affected, both physically and psychologically, and is also synonymous with social and professional disruption. 

In order to study the evolution of the impact of cancer over time on the daily lives of sufferers, the French National Cancer Institute decided to extend VICAN2 – the survey on life two years after a cancer diagnosis – which was conducted in 2012.

Conducted by Inserm[1], this study explores, five years after diagnosis, the health status, long-term side effects and medical follow-up, the difficulties experienced in daily life and also the impact of the disease and its treatments on resources and employment.  Its results will be discussed at a colloquium on June 10, in Paris.

 

“Life five years after a cancer diagnosis” – the VICAN5 study

Highly instructive, not just on the evolution of side effects but also on the impacts of the disease on the personal and professional lives of sufferers, the results can be used to orient the actions of public authorities and the various players committed to fighting cancer.

Some of these results back up the measures implemented by the French National Cancer Institute (INCa) and the public authorities (the supportive care package, the tertiary prevention measures such as the reimbursement of nicotine patches or the prescription of physical activity, the right to be forgotten or the return to work or continued employment as part of the “Club des entreprises”). Other results make it possible to consider actions to intensify the current measures or implement new ones to best orient the support given to patients and their relatives. Indeed, disparities in the prognosis, cancer site and status of sufferers make it possible to consider more targeted measures, notably regarding cancers in which the progress of the therapies remains low. As reaffirmed in the 2014-2019 Cancer Plan, continuity and quality of life despite the disease is an ambition shared by all those involved in fighting it.

 

The principal results of VICAN5

Cancer continues to impact physical quality of life

44.4 % of respondents report an impairment in physical quality of life compared with the general population. This percentage is similar to that observed with the first survey.

While lung cancer has the most negative impact on physical quality of life, a decrease can be observed in relation to the previous situation – as is the case with breast cancer.   For the other cancer sites, the situation remains stable.

The improvement observed with lung cancer remains to be qualified – indeed, it is the site with the highest mortality rate between the two surveys.  The results can therefore not be superimposed.

Fatigue is the most frequent spontaneously reported symptom – but its improvement depends on the cancer site

Five years post-diagnosis, 48.7% of respondents describe fatigue as a clinically significant symptom.  It is more prevalent in women and varies according to the cancer site.

In addition, levels of fatigue remain significantly higher in women and young people, with people in precarious economic situations reporting higher levels of fatigue, thereby highlighting the weight of inequalities in relation to its experience. 

The results show a significant decrease in the prevalence of fatigue for lung cancer and to a lesser extent for thyroid cancer, sites for which the prevalence of fatigue was highest at two years (decreasing from 70.9% at 2 years to 59.4% at 5 years and from 66% at 2 years to 55.8% at 5 years, respectively).

Beyond the differences between the sexes, those most vulnerable in relation to fatigue are the youngest, and those in a situation of economic hardship.  This last point underlines the ever-prominent weight of social inequalities in how the post-cancer period is experienced.

A decrease in resources linked mainly to a decrease in time worked

More than one quarter of those diagnosed in 2010 have experienced a decrease in their available income five years post-diagnosis. Those affected present the most vulnerable profiles on the job market (women, those educated to below baccalaureate level, the self-employed), often live alone and declare living with late side effects related to the disease and/or its treatment.

A decrease in time worked is the main cause of a decrease in professional income.

Strongly linked to disease characteristics such as cancer prognosis, receipt of chemotherapy and experience of fatigue in 2015, the decrease in the number of hours worked constitutes the lever most frequently used when resuming work in order to take into account the diminished physical capacity, which is mainly due to late side effects of the disease and its treatments.

VICAN5 also enables the follow-up at two and five years post-diagnosis of those who responded to both questionnaires.  Specific analysis of this group shows that the per capita decrease in income mainly occurs after the first two years following diagnosis; for 53.7% of respondents, this decrease occurs during the three subsequent years.

A deterioration in professional situation over time

Five years post-diagnosis, cancer still negatively impacts the professional lives of sufferers, depending on the epidemiological reality of the disease and the professional characteristics of the job held initially.

Those having had cancer have seen a deterioration in their professional situation, generally revealing an acceleration of the phenomenon of leaving employment: the decrease in employment rate and increase in unemployment are the primary results of the VICAN5 survey in relation to changes in professional status. An increase in the proportion of individuals on disability leave has also been observed.

Among those in work at the time of diagnosis, one in five is no longer working five years later.

Considering the fact that those on sick leave remain in work from an administrative viewpoint, this finding reveals a deterioration in the professional situation greater than that observed with VICAN2. It would therefore appear that the impact of cancer on professional life can occur in the medium-term.

As with the previous survey, those most concerned by job losses five years post-diagnosis are manual workers, private sector employees, individuals working in very small businesses, company heads and those having been diagnosed with lung, upper aerodigestive or colorectal cancer.

Some of the results presented here must be interpreted with caution.  The employment situation presented according to various socio-professional characteristics makes it possible to characterize the groups most concerned by a deterioration in their professional situation five years post-diagnosis, but this must not be interpreted too hastily in terms of causality.  For example, if those having suffered from lung cancer are more affected in terms of maintenance in employment, this can be due to the characteristics of the disease but also express an argument in the social epidemiology of cancer: the socio-professional categories most concerned by this type of disease, such as manual workers, are precisely those which are the most vulnerable on the job market.

Adjustment of working conditions deemed satisfactory

Adjustment of working time is the most common measure for those in employment at the time of diagnosis – 62.7% of respondents had their working conditions adjusted during the subsequent five years and declare themselves satisfied in the main. Those who benefited from the adjustments are women, people initially in full-time employment, public sector employees and people with permanent contracts. 
Self-employed workers had less recourse to such adjustments.       

Tertiary prevention: medical follow-up, lifestyle and consumption habits

At five years post-diagnosis, 56.9% of respondents are being followed up for their cancer in a primary-care setting.  However, more than one third (33.1%) declare that they are not being monitored and also feel less well-informed on the symptoms they are likely to face.

During and after cancer, diet and physical activity play a major role in various domains, such as prevention of the risk of a second cancer and improved disease prognosis and tolerance to treatments.  However, five years post-diagnosis, 34.3% of respondents declare to have not modified their exercise regimes.  Furthermore, 53% of respondents declare that they are getting less exercise or that they have stopped it altogether, whereas 12.7% state that they do more.

Those reporting an increase in their physical activity are younger and more often female, whereas those having experienced a decrease are those experiencing late side effects of the cancer, anxiety or depression, are more often male and more often older.  Three in five individuals having reduced their levels of physical activity present a marked state of fatigue.

As in the general population, among those diagnosed with cancer five years ago, the prevalence of smoking decreases with age and concerns more particularly those with low economic status.  As such, 39.8% of respondents who smoked prior to diagnosis no longer smoke five years later and 16.7% smoke tobacco most often daily.  Furthermore, and in contrast to what to the general population, women smoke more than men.

[1] Inserm JRU 1252-SESSTIM research team.

Method

The VICAN5 survey builds on VICAN2 by interviewing state health insurance beneficiaries resident in mainland France, in whom cancer was diagnosed around five years beforehand and who were aged between 18 and 82 at the time of diagnosis. Twelve cancer sites, including the most common, were focused on. In parallel to the telephone survey, medical record data and healthcare consumption information[2] were collected.
All in all, 4,174 people were questioned, among whom 2,009 individuals having participated in the previous survey, VICAN2, along with an additional sample of 2,165 people.

Download the summary of the study “La vie cinq ans après un diagnostic de cancer” (in French)

Download the full report  of the study “La vie cinq ans après un diagnostic de cancer” (in French)

[2] Data taken from the SNIIRAM database, which covers the various health insurance schemes.

Video Game Addiction Recognized by the World Health Organization

Posted on by Priscille Rivière

Crédits : AdobeStock

With the publication of the new International Classification of Diseases (ICD-11) on June 18, 2018, WHO officially recognizes the existence of a “gaming disorder”.

In its collective expert review of 2014 on addictive behaviors in adolescents, Inserm had already mentioned this form of addiction.

As part of the preparation of the French Government Plan 2013-2017 to combat drugs and addictive behaviors, the  Interministerial Mission for the Fight against Drugs and Drug Addiction (Mildt) had requested that Inserm prepare an overview of scientific knowledge regarding the susceptibility of adolescents (aged 10 to 18 years) to use psychoactive substances (whose consumption is notable in young people) as well as their susceptibility to develop other habits known to potentially cause problems, particularly video games.

This research is based on scientific data available in the second half of 2013. Approximately 1,400 articles constitute the documentary basis of this expert report.

Here is what was written on the subject of video games:

  • Use of video games /Internet

In 2011, out of the 80% of 17-year-olds who stated having used the Internet in the previous seven days, approximately one in four used it for 2-5 hours a day; fewer than one in five for 5-10 hours, and one in ten used it for over 10 hours a day.

Depending on the country and the measurement method used, the prevalence of problem Internet use by adolescents is thought to vary from 2 to 12%. In France, in 2011, initial estimations show that 3-5% of 17-year-olds may be involved.

Furthermore, 5% of 17-year-olds are thought to play video games for 5 to 10 hours a day.  Although the total time spent playing games is higher for boys than for girls, the time spent in front of a screen is identical, since girls are heavier users of social networking.

While video games may have positive aspects, especially regarding the development of cognitive and spatial functions, they may also lead to a loss of control and behavioral problems.  Among the various types of games, MMORPG (Massive Multiplayer Online Role-Playing Games), usually played by boys, have been described as particularly addictive.

Of the 17-year-old players (all types of video games), 26% stated that they had encountered problems at school or at work, and approximately 4% stated that they had experienced money problems in the previous year because of their playing habits.

Associated harm

Apart from the time spent, which can sometimes prove to be very long, problems of a psychological and somatic nature may occur in cases of excessive use: sleep disorders, irritability, sadness, anxiety, isolation, deterioration in academic performance, problems with parents, etc. Problem use of video games may encourage use of substances (tobacco, cannabis, alcohol, energy drinks, etc.), and increase the risk of a sedentary behavior and overweight.

Links:

Read the WHO press release: “WHO releases new International Classification of Diseases (ICD 11)”

Read the Inserm press release: “Addictive behaviours in adolescents”

Read the Inserm collective expert review (only available in French): “Conduites addictives chez les adolescents”

Usutu Virus Detected in a Patient in Montpellier in 2016

Posted on by Priscille Rivière

Usutu is an arbovirus from the same family as the Zika and West Nile viruses. Like its cousins, it is transmitted by mosquitoes. While we know that it is responsible for high mortality in birds, principally passerines, knowledge on human pathology remains limited.

As with other arboviruses, the majority of cases of human infection are probably asymptomatic. Nevertheless, rare neurological complications have been reported, justifying further research into its mechanism of action.

Only 26 cases of human infection by Usutu have been reported in Europe, a figure which is most certainly underestimated according to Yannick Simonin, lecturer-researcher specialized in the virus, given the non-existence of commercial screening tests and the general ignorance of the associated symptoms.

Animal studies show very strong neurological tropism of Usutu. Very recently, Simonin and his team from Unit 1058 “Pathogenesis and control of chronic infections” (Inserm/Université Montpellier/Montpellier University Hospital/ EFS) published in Emerging Infectious Diseases results showing its presence in the cerebrospinal fluid of a patient from Montpellier University Hospital in 2016, confirming this neurotropism. The clinical symptoms of the patient, which included temporary facial paralysis, had not until that point been linked to any specific disease. Additional investigations are necessary if we are to improve our understanding of the clinical picture associated with this emerging virus.

The research activities developed by JRU 1058 include determining the virulence, notably neuronal, of the various Usutu strains circulating in France in order to compare them in the laboratory and evaluate their pathogenicity. The Unit is also studying the transmission mechanisms of the virus in order to better elucidate the associated risks.

The Astre unit of CIRAD partner of Unit 1058 for this study, is also participating in vector mapping the Usutu virus.

Yellow fever: a new method for testing vaccine safety

Posted on by Lea Roy

A minibrain triculture. © Marie-Christine Cumont and Monique Lafon – Institut Pasteur.

Scientists from the Institut Pasteur, the CNRS and Sanofi Pasteur have recently developed a novel alternative method to animal testing that can be used to verify the safety of vaccines such as the yellow fever vaccine. This original approach is based on the development of an in cellulo device using a 3D culture model, the “BBB-Minibrain”, to evaluate the safety of live vaccines for human use. The model was developed by the Institut Pasteur and a patent application has been filed by the Institut Pasteur and Inserm. It raises hopes for a reduction in the use of animals in quality control, especially in the tests carried out by the pharmaceutical industry to meet the requirements of regulatory authorities. The results of this research were published in the journal Biologicals in May 2018, and online on March 24th.

For several years now, following the adoption of EU Directive 2010/63/EU,1 the scientific community has been actively seeking to reduce the practice of animal testing. But in many cases, these efforts are hindered by a lack of acceptable alternatives that satisfy regulatory authorities. This is particularly the case for the regulatory testing required for live viral vaccines, such as the yellow fever vaccine; suppliers must demonstrate that the seed lots used to produce vaccine batches sold on the market do not represent a risk of neurotoxicity. These tests are currently performed on animals, which are monitored for the emergence of any clinical signs in the central nervous system that may suggest neurotoxic side effects.

Against this backdrop, Institut Pasteur scientists developed a 3D culture model mimicking the human blood-brain interface, the “BBB-Minibrain”, in 2014. This model, formed of a blood-brain barrier (BBB) associated with a mixed culture of neurons, astrocytes and microglia (a “minibrain”), can be used to detect when viruses enter the brain through the BBB, their multiplication in the minibrain and the emergence of any neurotoxic effects. A patent application (WO2016038123) was filed for the model.

The scientists set out to test the BBB-Minibrain’s ability to pinpoint and amplify any rare mutant particles with neuroinvasive and neurovirulent properties that are found in seed lots for live viral vaccines. They chose to use two yellow fever virus vaccine strains, including the strain currently used to produce the vaccine, which does not cause neurotoxicity.

Working with Sanofi Pasteur research teams, they demonstrated that the BBB-Minibrain can be used to identify any rare viral particles in vaccine preparations that have acquired the ability to enter the brain and multiply there. This test therefore paves the way for the rejection of any seed lots containing mutant viruses capable of entering the brain and becoming neurovirulent.

As Monique Lafon, lead author of the study and Director of the Virology Department at the Institut Pasteur, explains, “replacing animal testing is a major challenge for research. The BBB-Minibrain model is an ingenious tool that will facilitate our analysis of the basis for neurovirulence in these viruses, which colonize the brain via the bloodstream.”

These findings represent a first proof of concept and feasibility for the development of an alternative test that complies with the “3Rs” principle. Work to develop this test is ongoing. The long-term aim is to secure approval for the new test from regulatory authorities.

The BBB-Minibrain model raises hopes for the development of an alternative method that can be used by the pharmaceutical industry to perform regulatory tests on live viral vaccines. The aim of this method is to reduce the use of animals while ensuring strict monitoring of any scientific benefits and breakthroughs in the area of human health.

 

1 This Directive enshrines the 3Rs approach: the treatment and use of living animals for scientific purposes are governed by the principles of Replacement, Reduction and Refinement as established at international level.

Anaelle Da Costa received the 2017 Hub France R&D Award (November 2017), Sanofi Pasteur, and the 2017 Global R&D Awards – We R Hope Award for Innovative Postdoctoral Research (May 2018), Sanofi Pasteur.

A medical first: CLOVES Syndrome and overgrowth syndromes: remarkable improvement in the health of 19 paediatric and adult patients using a new therapeutic strategy

Posted on by Priscille Rivière

Credits: C Kowalski/Université Paris-Descartes

Dr Guillaume Canaud at the Necker-Enfants Malades Hospital – AP-HP, the Paris Descartes University, Inserm (INEM Institute Necker Enfants Malades – Centre for Molecular Medicine) and his team recently demonstrated the efficacy of a novel medication, a specific inhibitor called BYL719, in a cohort of 19 patients treated at the Necker-Enfants Malades Hospital – AP-HP and suffering from CLOVES Syndrome (Congenital Lipomatous Overgrowth, Vascular Malformation, Epidermal Naevi) or similar disorders. This medication is currently undergoing therapeutic oncology trials (phase I/II). No significant side effects have been observed 18 months after commencement of treatment. This study, published in the journal Nature, is an example of precision medicine and demonstrates the major benefits of this therapeutic strategy for these patients, who have seen their health and quality of life improve significantly.

Patients suffering from CLOVES Syndrome (Congenital Lipomatous Overgrowth, Vascular Malformation, Epidermal Naevi) or similar disorders have major deformities and vascular masses due to mutations of a gene called PIK3CA. This gene regulates cell proliferation and growth. When overly activated, it causes the excessive growth of those parts of the body affected by the mutation. Accordingly, patients present with symptoms that vary greatly depending on the number of tissues affected, which may range from isolated macrodactyly (enlarged fingers or toes to very severe forms affecting the entire body such as CLOVES syndrome.

The most serious forms involve the overgrowth of fatty tissue, vascular malformations, scoliosis, skeletal anomalies such as major bone enlargement and the deformity of organs such as the brain or kidneys. Until now, no curative treatment has been available for those patients for whom the syndrome is potentially life-threatening in the short-to-medium-term and for whom the only therapeutic options have been symptomatic treatments. In the most severe cases patients undergo embolization procedures or mutilating surgery. Finally, it is important to note that these syndromes are frequently associated with chronic pain and have major repercussions on a patient’s quality of life and social life.

The PIK3CA gene frequently mutates in several cancers (particularly breast and colon cancers) and is a therapeutic target for the pharmaceutical industry. PIK3CA mutations in cancers are the same as those found in patients suffering from CLOVES syndrome and similar disorders.

At the end of 2015, a 29-year-old patient with a CLOVES syndrome was referred to Dr. Guillaume Canaud, a specialist of the PIK3CA pathway. This patient had a very advanced and life-threatening form of CLOVES syndrome and for whom no surgery or radiological embolization could be proposed. Dr. Guillaume Canaud then approached the Novartis laboratory working in the field of oncology on a specific inhibitor of the PIK3CA gene called BYL719. This medication is currently undergoing therapeutic oncology trials (phase I/II).

In January 2016, having obtained the authorisation of the ANSM (French National Agency for Medicines and Health Products Safety) to use this experimental treatment, Dr. Guillaume Canaud administered the treatment on this first patient. Very quickly, a positive effect was observed on all symptoms. In particular, a significant decrease was observed in the size of vascular masses and overgrowths from which the patient suffered and a major improvement was seen in his quality of life. Eighteen months later, this first patient had experienced only one side effect, hyperglycaemia, which was well controlled by diet.

At the same time, in order to better understand this disease and the mechanism of action of the medication, Dr Canaud and his research team within the INEM-Inserm Unit U1151) created the first mouse (murine) model that recapitulates all the lesions observed in patients with CLOVES syndrome. The mice were treated with the medication BYL719 and here too a major and rapid improvement in their health was observed.

On the basis of these results, in June 2016, Dr. Canaud quickly gathered a working group composed of ten medical and surgical specialisations to care for patients suffering from CLOVES Syndrome or similar syndromes at the Necker – Enfants Malades Hospital – AP-HP. The idea behind the group was to provide better care for patients.

During the summer of 2016, a 9-year old girl suffering from a serious form of CLOVES Syndrome with a life-threatening vascular mass for which no surgical intervention or embolization was possible, received this experimental treatment. Once again, BYL719 had a spectacular effect on all symptoms, deformities and the vascular mass. It is important to note that no side effects were observed in this first child, the first in the world to receive this treatment, and that her growth was not affected during the 12 months of treatment.

In February 2017, on the basis of these results, Dr. Canaud and his group were authorized by the ANSM to administer the BYL719 to17 additional patients (14 children and 3 adults with ages ranging from 4 to 50 years) followed at Necker hospital, who had life-threatening complications and/or were scheduled for debulking surgery. Very quickly after treatment initiation, they observed a spectacular improvement in their general health of all patients. All patients had a rapid reduction in the size and volume of vascular tumours, but also the enlarged veins and abnormal limbs, they also noticed an improvement in the skin appearance a decrease in fatigue. Moreover, an improvement in scoliosis was observed in all patients. Patients were accordingly able to return to physical activity, stop morphine-based treatment, go back to school, etc.

After six months of treatment, these 17 patients are still alive and have not undergone any surgical interventions. Minor side effects, such as mouth ulcers, were observed in three patients.

 

These 19 patients continue to receive BYL719 daily.

© Dr Canaud, AP-HP

This study, the protocol for which was approved by the French National Agency for Medicines and Health Products Safety (ANSM), demonstrates the efficacy of this therapeutic approach.

In the opinion of Dr Canaud, “this treatment will radically change the future for patients suffering from overgrowth syndromes associated with PIK3CA mutation. The medication has enabled us to obtain results that exceeded our expectations with the regression of malformations that had existed for a number of years, and also an improvement in the quality of life for patients and their families. BYL719 therefore offers great hope as a treatment for even very severe forms of the disease. Finally, our study demonstrates the benefit of developing targeted treatments for genetic diseases to develop what is termed precision medicine, and  also the need for a very high degree of interaction between clinicians and researchers to advance knowledge and develop new medications”. “

 This work has led to a patent registration application being submitted by Inserm Transfert for AP-HP, Paris Descartes University and Inserm.

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