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Month: December 2017

An international study identifies new loci associated with asthma wich are enriched in epigenetic marks

Posted on by Priscille Rivière

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An international study led by scientists from Inserm and Paris Diderot University (France), the University of Chicago (USA), the National Heart and Lung Institute (UK) and the University of Colorado Anschutz Medical Campus (USA) together with researchers of the Trans-National Asthma Genetics Consortium (TAGC) has discovered five new regions of the genome that increase the risk of asthma. This study is published online in Nature Genetics on 22 December 2017.

A major finding of this study is that the genetic loci associated with asthma are enriched in epigenetic marks characterizing gene enhancers. Another key element is the shared associations of variants with asthma, auto-immune diseases and diseases with an inflammatory component. The outcomes of this work open new avenues of research with the goal of elucidating the biological mechanisms underlying asthma in relationship with environmental exposures and to promote the development of new therapies

Asthma is a chronic inflammatory disease that affects more than 300 million people worldwide and has a significant socio-economic impact. Asthma is characterized by clinical heterogeneity. Asthma results from both genetic predisposition and exposure to environmental and lifestyle factors.

The TAGC study brought together more than 45 research groups from Europe, North America, Mexico, Australia and Japan. It allowed pooling data on millions of DNA polymorphisms (genetic variants) throughout the genome in more than 142,000 asthmatic and non-asthmatic subjects of European, African, Latino and Japanese ancestry. Meta-analyses of genome-wide association studies conducted in these ethnically-diverse populations identified a total of 878 genetic variants belonging to 18 loci associated with asthma risk.

The TAGC study showed that genetic variants associated with asthma are preferentially located near critical gene regulatory sites called “enhancers” in immune cells, suggesting a role of these variants in the regulation of immunologically related mechanisms.

Another key element concerns the involvement of several identified candidate genes in the immune response to viruses, thus highlighting the importance of viral infections in the risk of asthma.

The genetic variants associated with asthma have also effects on  autoimmune diseases and other diseases with an inflammatory component (such as cardiovascular diseases, cancers, neuro-psychiatric diseases), which strengthens the importance of pleiotropy in multifactorial diseases.

In conclusion, these results highlight the importance of large-scale genetic studies to better characterize complex diseases. This study opens new avenues of research aiming at integrating genomic and epigenomic data together with environmental exposures in order to elucidate the physio-pathological mechanisms underlying asthma and to promote the development of new therapies.

Vaccines: Good News for Our Children!

Posted on by Priscille Rivière

Reluctance, or indeed mistrust, towards immunization, is an understandable sentiment, particularly among young parents when their babies are about to be immunized. While this principle may currently seem less vital, or even optional, to parents who no longer face the same tragedies arising from infection as in the past, it nonetheless remains an essential public health measure.

Mandatory immunization came into force on January 1, 2018, and has thus given rise to concerns and debate in public opinion. Numerous scientific falsehoods are doing the rounds, underlining the so-called hazards of vaccines, and debating the relevance of immunization. On December 18, Inserm published a Clarification which aims to provide the scientific perspective on the 11 vaccines which will be mandatory for all infants in France in 2018.

In the face of these rumors, Alain Fischer, pediatrician, immunology researcher, coordinator of Concertation Citoyenne sur la vaccination, and Philippe Sansonetti, specialist in infectious diseases, microbiology researcher, author of “Vaccins”, both professors at the Collège de France, have joined forces to offer an in-depth review of every aspect of immunization.

Read the press kit from the conference organized on December 22 

Read the press release on the clarification issued by Inserm

Watch the video “c’est quoi un vaccin? (What is a vaccine?)” (only available in French)

Microbiome Influences Brain’s Immune Cells in a Sex and Age-dependent manner

Posted on by Priscille Rivière

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A joint study conducted by Inserm researchers from IBENS (Institute of Biology of the Ecole Normale Supérieure – Inserm/CNRS/ENS) in Paris and researchers from SIgN (Singapore Immunology Network, A*STAR) in Singapore reveals a hitherto undiscovered impact of microbiota on immune brain cells, occurring from fetal stages. These cells, called microglia, which are known players in brain development and functioning, differentially respond to microbiome perturbations in male or female mice. These results are published in Cell.

Microglia are immune cells that respond to traumatic injury or inflammatory signals to protect the brain, acting as sensors of various environmental signals. In addition to their role as immune sentinels, microglia have also been show to regulate several steps of brain wiring and functioning. Consistently, microglia dysfunction has been linked with the etiology of several neurodegenerative diseases and neurodevelopmental disorders, including Schizophrenia or Autism Spectrum Disorders. Microglia therefore play major roles in brain circuits and could constitute an entry point for environmental signals.

To test this hypothesis, Morgane Thion and Sonia Garel, Inserm researchers, together with their associates, used a multidisciplinary approach involving germ-free mice, which lack all the microbiome, and adult mice treated with antibiotics, which acutely destroys the gut flora. Through a combination of global genomic analyses and histological studies, researchers have shown that microglia are profoundly affected by microbiota disruption, already from prenatal stages. Strikingly, the impact of the microbiome on microglia depended on the sexual identity and the age: microglia of males were perturbed prenatally whereas those of females were affected in adulthood. This surprising sexual dimorphism echoes the fact that many neurodevelopmental disorders have a higher incidence in men, whereas autoimmune diseases are more prevalent in women.

While the underlying mechanisms and consequences remain to be discovered, this study reveals a key role of microglia at the brain/environment interface and shows that males and females have distinct susceptibilities time windows to microbiome alterations. For the authors, these elements should be systematically taken into consideration at preclinical and clinical level.

The first French cell therapy trial in a form of retinitis pigmentosa on the horizon

Posted on by Priscille Rivière

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A team of scientists led by Christelle Monville (professor at University of Evry) at I-Stem, the laboratory created by AFM-Téléthon, University of Evry and Inserm, in partnership with the team led by Olivier Goureau, Inserm Research Director within the Institute of Vision, has managed to improve vision in rats with retinitis pigmentosa, by transplanting a cell bandage obtained from human embryonic stem cells. The results published today in Science Translational Medicine, notably achieved thanks to Téléthon donations, pave the way for cell therapy retinitis pigmentosa, but also for very common retinal degenerative diseases, such as certain forms of age-related macular degeneration (AMD).

In France, nearly 30,000 individuals are affected by retinitis pigmentosa – a group of rare diseases affecting vision – and more than 1.5 million by age-related macular degeneration (AMD). These incurable diseases are characterized by gradual degeneration of the retinal cells, ultimately leading to blindness.

In order to replace deficient cells in patients, the initial studies, conducted in humans by American teams from 2012 onwards, involved injecting the eye with retinal pigment epithelial cells placed in suspension – i.e., separated from each other – obtained from human embryonic stem cells. However, this technique was not optimized in terms of the assimilation and survival of the delivered cells. In the study by French scientists, published today, these problems were circumvented owing to an innovative approach: after the human embryonic stem cells had differentiated into epithelial cells, they were inoculated on a segment of human amniotic membrane to create a “cell patch”. This patch was then transplanted into the most peripheral layer of the retina in rats spontaneously presenting genetic retinitis pigmentosa. At the same time, other rodents were administered an injection of suspended cells with a view to comparing both techniques.

Watch the video (DR I-

After 13 weeks of observation, the scientists noted that the rats having been transplanted with a patch showed the best visual performance, and over a longer time-frame, relative to the animals having received the suspended cells.

On the strength of these results, in the coming weeks, the scientists will be submitting an authorization application for a phase I/II clinical trial in approximately twelve patients with retinitis pigmentosa, which is thus expected to start in about a year’s time, at Hôpital des Quinze-Vingts, under the supervision of Professor José-Alain Sahel. This will be the first cell therapy trial in the field of vision disorders, in France.

 Ultimately, this new approach could be applied to all disorders in which damage to the retinal pigment epithelium is observed, notably in dry (or atrophic) forms of AMD.

According to Christelle Monville, research professor at University of Evry and at I-Stem “We have been working with the whole team for the past 6 years to develop this innovative technique. This is, in fact, the first time that a “cell patch” has been created with embryonic stem cells and a human amniotic membrane. We have shown that this technique, being more effective, opens up new therapeutic prospects for retinal diseases, whether rare genetic diseases or common age-related diseases. Now we are about to begin trials in patients, this is a very exciting time indeed.”

Marc Peschanski, I-Stem Director, confirms this: “This new proof of concept shows the extent to which research in the field of cell therapy – driven by the team at -Stem – is making progress, together with the therapeutic prospects that it offers. We have now spent over 10 years working on developing this new medicine, and I am proud that my teams are on the verge of initiating the first French cell therapy trial for rare vision diseases.”

According to Olivier Goureau, Inserm Research Director at the Institute of Vision, “The realization of this collaborative project, and the forthcoming transfer to patients are driving us even more to continue developing these cell therapy strategies related to the use of pluripotent stem cells to help patients.“

Gene Therapy Cures Hemophilia

Posted on by Priscille Rivière

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Hemophilia is a serious hereditary disease that prevents the blood from clotting. This means that, in the event of a wound, bleeding doesn’t stop or is extremely difficult to stop.

There are two types of hemophilia:

– Hemophilia A, the more common form, is linked to a deficiency in clotting factor VIII

– Hemophilia B, occurring more rarely, is linked to a deficiency in clotting factor IX

Hemophilia primarily affects boys and occurs very rarely in girls, since the disease is passed down on the X chromosome.

Two clinical studies recently published in The New England Journal of Medicine show that it is now possible to cure both hemophilia A and hemophilia B through gene therapy. A one-hour transfusion of a rescue gene that codes for the faulty clotting factor was enough to cure patients suffering from the disease. This is a breakthrough in treating the disease, and it is also one step further for gene therapy, which is being used more and more often in clinical trials.

 

Read our other content on hemophilia:

Jumping Genes: All Guilty?

Sunday, April 17: World Hemophilia Day

Hemophilia: A Hereditary Hemorrhagic Disease

A new therapeutic target in allergic asthma

Posted on by Priscille Rivière

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Vincent Sauzeau, Inserm researcher and his team located at the Nantes Thorax Institute[1] (Inserm, CNRS, University of Nantes, Nantes University Hospital) have recently discovered the major role played by the Rac1 protein in the development of bronchial hyperresponsiveness associated with allergic asthma. Researchers will use this new therapeutic target to reduce bronchoconstriction and pulmonary inflammation in patients. This article has been published in The Journal of Allergy and Clinical Immunology.

Allergic asthma is a major public health problem, which currently affects 8 to 10% of the global population. It represents 70% of the various types of asthma, and is responsible for more than 250,000 deaths per year. Asthma attacks are triggered by an allergen, which induces excessive contraction of muscle cells in the bronchial wall (bronchial hyperresponsiveness). This reduces the diameter of the bronchi and causes breathing difficulties in the patient (sense of suffocation, shortness of breath, cough, wheezing, etc.).

Vincent Sauzeau, Inserm researcher and his team have recently evidenced the essential role played by the Rac1 protein in bronchial muscle contraction and bronchial hyperresponsiveness associated with allergic asthma, making Rac1 a new therapeutic target in allergic asthma.

A promising avenue for treating patients

The researchers used a dust-mite sensitized asthmatic mouse model to imitate the human disease, in order to determine the role of Rac1 in bronchial hyperresponsiveness. They noted that inhalation of a Rac1 inhibitor prevents bronchial hyperresponsiveness in this allergic asthmatic mouse model. Furthermore, bronchial inflammation and the infiltration of certain white blood cells into the lungs (which promote bronchial hyperresponsiveness in allergic asthma) are also reduced by long-term administration of the Rac1 inhibitor. The research team observed a 70 to 80% reduction in bronchial contraction due to Rac1 inhibition, on bronchial samples taken from lung transplant patients.

“Blocking the activity of Rac1 made it possible to both limit bronchial contraction during an asthma attack, and also to reduce local inflammation during maintenance therapy,” clarifies Vincent Sauzeau, Inserm researcher leading these studies. The inhibitors used in these studies are research instruments, which can only be used in a laboratory setting. Hence, the researchers are currently developing new molecules for clinical applications.

This research team, in partnership with the Pulmonology Department at the Thorax Institute based at Nantes University Hospital has recently obtained funding to verify the relationship between bronchial hyperresponsiveness and abnormal Rac1 activation in the bronchi in patients suffering from allergic asthma. “If this relationship is confirmed, this will validate the significance of developing a new Rac1 inhibitor for therapeutic purposes in humans. It would then be administered by inhalation, for a targeted action in the bronchi,” concludes Vincent Sauzeau. At present, 5 to 10% of patients suffering from allergic asthma do not gain any relief from standard anti-inflammatory and bronchodilator treatments. Rac1 inhibitors could offer new therapeutic solutions.

[1] (http://www.umr1087.univ-nantes.fr/)

What does science say about the eleven vaccines that will be mandatory for all children in France starting in 2018? INSERM has just published an official report.

Posted on by Priscille Rivière

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In the context of the extension of mandatory vaccination that will go into effect in 2018, immunization is becoming a topic of public debate. People are often ill-informed, basing their opinions on the catastrophist arguments of anti-vaccine lobbies and the lack of relevant training on the part of medical professionals. France has become one of the countries where defiance against vaccination is at its strongest worldwide. The controversy is happening despite the facts that the mandatory vaccinations match the current immunization calendar and that no additional vaccines have been added. The purpose of this measure is to ensure that children are actually receiving the vaccines that are scheduled for all children.

In four chapters, this INSERM report reviews the scientific knowledge that must underlie a rational decision on the part of lawmakers:

  1. The eleven vaccines that will become mandatory in France have been scientifically proven to be safe and effective.
  2. The increase in vaccination coverage of babies will provide individual benefits by directly protecting the vaccinated child, as well as collective benefits by reducing the risk of contamination for unvaccinated individuals.
  3. Foreign decision-makers have divided opinions on whether to simply recommend vaccination or to make it mandatory.
  4. The temporary extension of the mandatory character of eleven vaccines recommended for children, as endorsed by the Citizen Advisory Orientation Committee on Vaccination, must be accompanied by the implementation of priority actions and the development of research programs that cover the various aspects of vaccination. 

View INSERM’s complete report in french here

Moderate to high primary care activity in France !

Posted on by Priscille Rivière

The Sentinel network, a collaborative surveillance system developed by Inserm and Pierre and Marie Curie University (UPMC), is made up of 1,300 primary care practitioners, and approximately one hundred independent pediatricians, spread over mainland France. The network is coordinated by the “Transmissible Diseases Surveillance and Modeling” team at the Inserm and UPMC Pierre Louis Epidemiology and Public Health Institute (iPLESP), in collaboration with the French National Public Health Agency (ANRS) and Santé Publique France (French Public Health Agency). The data are transferred in real time, based on 9 health indicators. Analysis of these data thus makes it possible to estimate the weekly incidence rate for each indicator, and to monitor changes at national level.

According to the weekly Sentinel network newsletter dated December 13, 2017, the incidence rate for cases of acute diarrhea is above the epidemic threshold (188 cases per 100,000 inhabitants). According to the Sentinel network, it is still too early to talk about an epidemic, strictly speaking, and the level of activity for acute diarrhea should remain stable in the next few weeks.

The Sentinel network states that the highest incidence rates for acute diarrhea have been observed in the Provence-Alpes-Côtes d’Azur, Pays de la Loire, and Hauts-de-France regions.

On the other hand, influenza syndrome, until now well below the epidemic threshold, has increased from 19 cases, to 98 cases per 10,000 inhabitants. The highest incidence rates have been observed in the Provence-Alpes-Côte d’Azur, Brittany, and Centre-Val de Loire regions. The Sentinel network, which now comprises a new instrument for detecting influenza epidemics developed with Santé Publique France (French Public Health Agency), indicates a marked increase in influenza activity in mainland France.

Identification of Early Markers of Neurodegenerative Diseases in At-risk People

Posted on by Priscille Rivière

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A study sponsored by the AP-HP has shown for the first time that asymptomatic individuals who carry the c9orf72 mutation, which means they are at risk of developing frontotemporal degeneration (FTD) or amyotrophic lateral sclerosis (ALS), experience cognitive, anatomical, and structural changes very early on, before age 40.

The ability to identify these markers before disease symptoms appear is a major discovery, as such markers are crucial in developing therapeutic trials and monitoring their efficacy.

This study conducted by the Brain & Spinal Cord Institute – INSERM / CNRS / UPMC – at the Pitié-Salpêtrière AP-HP Hospital by Dr. Isabelle Le Ber, Anne Bertrand, and Olivier Colliot (CNRS researcher) was funded by the Translational Health Research Program (PRT-S).

The results of the study were published on December 2, 2017 in JAMA Neurology.

 

Frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that can have a common genetic cause, the most frequent of which is a mutation of the c9orf72 gene. Certain pre-clinical developments targeting this gene offer encouraging therapeutic directions. Identifying markers to detect the appearance of lesions at an early stage and to monitor the evolution of the disease is crucial in order to be able to test the efficacy of these potential therapies.

Indeed, it has now been established that these neurodegenerative diseases cause biological and morphological changes several years before the first symptoms of the disease appear. These pre-symptomatic stages are probably the best window of therapeutic intervention to stop the neurodegenerative process before it causes irreversible damage to the brain. The objective is therefore to identify markers of the beginning of the lesion-forming process or clinical conversion, meaning the appearance of the first clinical symptoms of disease progression.

This multimodal study was conducted at the Pitié-Salpêtrière AP-HP Hospital on a large cohort of 80 asymptomatic subjects carrying the c9orf72 mutation, meaning they were at risk of developing FTD or ALS within a few years. The subjects were monitored for 36 months using neuropsychological, structural, and micro-structural analyses of cerebral white matter and cerebral metabolism. Clinical examinations and lab work were also carried out, all with the aim of identifying clinical, biological, neuro-imaging, and cerebral metabolism markers.

The results of this study showed for the first time that very early cognitive and structural changes in subjects under 40 years of age are detectable, on average, 25 years before the onset of symptoms. Problems with praxis (difficulties carrying out certain movements) appear early on. These symptoms are not typical of FTD, and one of the hypotheses is that they could be caused by an early change in the development of certain regions of the brain, which could be related to the mutation. Interestingly, changes in cerebral white matter, detected early by MRI, predominate in the frontal and temporal regions, the disease’s target regions, and could be one of the best biomarkers of the disease. As a whole, this study provides a better understanding of the spectrum of the disease caused by changes to c9orf72.

Revealing biomarkers at very early stages is a first step towards developing the necessary tools for evaluating new treatments. Indeed, to prevent the onset of the disease, medications must be administered at the presymptomatic stages. This requires the development of tools that allow us to know when to start treatment and that can be used to measure its efficacy.

10 Principles for Fighting Climate Change

Posted on by Priscille Rivière

Photo by Aaron Burden on Unsplash

Since the COP 22, health has been a central topic of discussion. It is within this context, and on the day before the One planet Summit to be held tomorrow in Paris, that 10 principles for protecting respiratory health from climate change were proposed by an ad hoc workgroup from the Environment and Health Committee of the European Respiratory Society. Those principles have just been published in European Respiratory Journal: http://erj.ersjournals.com/content/50/6/1701912

Isabella Annesi-Maesano, INSERM Research Director, is a co-author of this article.

 

  1. Climate change is real. The first principle reasserts that climate change and global warming are real[i], which is a precondition to any defensive actions against climate change.
  2. Health and the environment are inextricably linked to climate change. Despite this, political action and investments currently underway are not yet enough to confront these challenges on the worldwide scale.
  3. Climate change has a direct effect on respiratory health. Cold temperatures, rising temperatures, humidity, variations in atmospheric pressure, storms, flooding, and other phenomena are a serious threat to respiratory health[ii].
  4. Climate change also has an indirect effect on respiratory health. Climate change can also trigger heightened exposure to other respiratory illness risk factors, for example atmospheric pollution, pollen, and infectious agents, and this can cause them to develop and become worse more quickly[iii] [iv].
  5. Few data are available. Yet understanding these phenomena better would make it possible to carry out risk simulations and better organize prevention.
  6. The impact on health is not the same for everyone. Certain populations are at greater risk since they are more vulnerable. For example, 30% of the world’s population is threatened by “deadly heat waves.” The impact is felt even more intensely by those who suffer from respiratory illnesses or who are predisposed to them. [v]
  7. The challenge is to change. The anthropic greenhouse gas emissions responsible for global warming and climate change can be primarily attributed to humans (population size, economic activities, lifestyle, energy consumption, soil use methods). Fighting climate change requires a combination of reduction measures to treat the causes and adaptation measures to treat the impact.
  8. Reduction (mitigation). Climate change can be mitigated by drastically reducing greenhouse gas (GHG) concentrations or, at the very least, stabilizing them in the atmosphere at a level that prevents all dangerous anthropic disturbance to the climate system. This can be achieved by reducing GHG emissions and pollutants. This includes the action of atmospheric pollutants with a short lifespan in order to reduce the greenhouse effects in the short term, which involves the protection and improvement of GHG sinks and reserves (e.g., forests and soil).
  9. Local action plans can be made to protect health in the event of a heat wave or excessively cold temperatures, to deploy specialized emergency medical services, to improve the monitoring and supervision of climate-sensitive illnesses, and to sanitize drinking water. The “polluters pay” concept must no longer be accepted, as less harmful alternatives are an option.
  10. Action must be taken now. And it must be taken by governments and nations. In Europe, the following must be done (among others):
  • invest in green fuels and technologies
  • take political measures to reduce Diesel emissions
  • adopt and apply the WHO air quality standards as EU limits
  • prosecute those who violate EU legislation

Conclusion

Healthcare professionals have a duty to contribute to the application of these principles.

[i] . Climate change is happening now[i]. The rise in global average temperatures is quite clear. The deviation from the average for the period of reference, ranging from 1961 to 1990, has almost always been positive since the early 1980s. The decade from 2001 to 2010 was 0.21°C warmer than the decade from 1991 to 2000, and is 0.48°C higher than the 1961-1990 average. 2016 was the warmest year (by 1.2° Celsius) on the planet since temperatures began being recorded in 1880, marking the third consecutive annual heat record according to the National Oceanic and Atmospheric Administration (NOAA). The land and ocean surface temperature was 0.94ºC higher than the twentieth-century average of 13.9ºC, which was 0.9ºC higher than the previous record for 2015, according to NOAA. Land surface temperatures alone were 1.43ºC higher than the twentieth-century average, and ocean surface temperatures were 0.75ºC higher (or 0.1 point higher than the 2015 record). Rising temperatures and the resulting extreme weather (flooding, heat waves, storms) are caused by the increase in carbon dioxide (CO2) and other greenhouse gases (methane, nitrous oxide, fluorocarbons) in the atmosphere due to human activity.

[ii] Climate change and respiratory diseases ERR 2014 23

[iii] Mendell MJ, Mirer AG, Cheung K, et al. Respiratory and allergic health effects of dampness, mold, and dampness related agents: a review of the epidemiologic evidence. Environ Health Perspect 2011; 119: 748–756.

[iv] Ayres JG, Forberg B, Annesi-Maesano I, et al. Climate change and respiratory disease: European Respiratory Society statement. Eur Respir J 2009; 34: 295–302

[v] Annesi-Maesano I.UN Climate Change Conferences: COP21 a lost opportunity for asthma and allergies and preparing for COP22. J Allergy Clin Immnol 2016;138:57-8

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