Repurposing Drugs to Fight the Flu: a Phase 2 Clinical Trial for FLUNEXT


The VirPath team from the International Center for Infectiology Research (CIRI, Inserm Unit 1111 – CNRS Joint Research Unit 5308  – ENS Lyon – UCBL1), in collaboration with the laboratory of Dr. Guy Boivin (Canada Research Chair in Emerging Viruses, Infectious Diseases Research Center of the University Hospital of Quebec – Université Laval), has developed and validated an innovative strategy which involves the identification and direct exploitation of clinical samples from infected patients in order to select and use drugs marketed for the treatment of other viruses. A strategy known as “drug repurposing”. This program has been funded by Inserm, the French Directorate of Health Care Supply (DGOS), the French National Research Agency, the Auvergne Rhône-Alpes region, Université Claude Bernard and Université Laval.

This novel and accelerated bedside-to-bench and bench-to-bedside approach is particularly well-suited to acute respiratory infections because it enables the identification and rapid validation of new generations of antivirals which are more effective and treat a broader spectrum of diseases. In addition, the regulatory and financial benefits of this drug repurposing strategy are evident when compared with the long and very costly traditional new-drug development process. The team’s Drug Discovery platform has already demonstrated its potential (three international patents protecting eight repurposed drugs) with the identification of diltiazem (Tildiem®) – usually used in heart pathologies – as an anti-infectious agent in flu viruses.

On the basis of these findings, a phase 2 clinical trial, called FLUNEXT, led by Manuel Rosa-Calatrava, Inserm researcher and Julien Poissy (Inserm Unit 995, Lille Inflammation Research International Center) of Lille University Hospital, began in January 2018. The objective of this national trial is to evaluate the effects of diltiazem in combination with an antiviral, oseltamivir (Tamiflu®), for the treatment of severe flu infections. It intends to enroll 300 patients in ten intensive care units, over two periods of flu epidemic, with final results expected in 2019.

The validation of this strategy and the results already obtained have led to the creation of a startup called Signia Therapeutics. The laboratory’s research program will now be extended to include other respiratory diseases, such as human respiratory syncytial virus and human metapneumovirus, responsible for severe respiratory infections in young children and the elderly.

For more information on the VirPath team and CIRI:

The VirPath website

The CIRI website

A patient has been living with an artificial larynx for the 18 months

U1121 "Biomatériaux et Bioingénierie"

© Inserm/Delapierre, Patrick

In 2013, researchers from Inserm and physicians from the Strasbourg University Hospitals announced their success in developing an artificial larynx. Since the first time they began implanting this prosthesis five years ago in patients whose own larynx had been removed for health reasons, they have optimized both the implant and their surgical technique. Today, they are presenting the case of a patient who has had the implant for 18 months, a feat that has enabled him to regain his voice and sense of smell, breathe through his nose and mouth, and not have to use his tracheostomy tube.

In cases of severe laryngeal cancer, doctors can opt to perform total laryngectomy. However, in order to be able to breathe correctly, the patient will then need a tracheostomy, which is an opening created in the front of the neck. The impact on quality of life means that such a procedure is not without consequences for the patient, due in particular to the loss of voice and sense of smell. After a lengthy rehabilitation period, the patient can use the esophageal speech technique but the process is an arduous one.

Christian Debry, researcher at Inserm Unit 1121 “Biomaterials and Bio-engineering” and Head of the Department of Otolaryngology and Head and Neck Surgery at Strasbourg Hautepierre University Hospital, together with his co-workers has endeavored to develop an artificial larynx for these patients[1]. Since 2012, 6 patients have received such implants but their fragile state of health has meant that they have not been able to keep them. Last year, Inserm researchers had optimized the surface coatings of the implants by developing an antimicrobial film to prevent them from being rejected.

“This 56-year-old patient has been living with the optimized implant for more than 18 months. He has now regained his voice and sense of smell, which had been compromised by the surgery.  He is able to completely go without using his tracheostomy tube for long periods – both day and night. It is the first time that such a concept has proved itself. The patient does continue to have some difficulty swallowing but, nevertheless, an initial breakthrough has been made, which is an actual improvement in comfort and quality of life for these patients. Our ambition is to ultimately restore their ability to eat normally and that they rediscover the social aspect of mealtimes. The development prospects for this prosthesis remain considerable.” emphasized Christian Debry.

[1] with the company Protip Medical

Biological Engineering: Marine Vessels

Researchers are aiming to produce flexible and malleable substitute materials to replace defective small blood vessels. The team led by Didier Letourneur, in Inserm Unit 1148, took inspiration from the composition of algae when designing polysaccharide-based vessels.

Read the whole article in Science & Santé magazine issue no. 31 (April/May 2016)

These synthetic vessels have been successfully grafted in rats. “At three months post-graft, three quarters of the vessels that had been grafted in the place of the abdominal aorta were functional,” states Cédric Chauvierre, laboratory physical chemist.


Marine vessels

What if the sea could suggest tissue engineering methods? This is indeed the case in the translational vascular research laboratory: the researchers drew inspiration from the flexible properties of algae to create synthetic blood vessels. Whether used as a research model or to train surgeons, these vessels have already been successfully grafted in rats.

Two millimeters in diameter, synthetic vascular prostheses are the size of small vessels in the human body.


Looking at the brain to prevent depression in adolescents

Depression is a real public health issue with 8% of adolescents affected by it, according to the French National Authority for Health (HAS). Adolescence is a time of transition during which young people are prone to episodes of depression. This often complicates the diagnosis of this disease.

According to some studies, adolescents with severe depression appear to have deviations in the areas of the brain associated with reward response. It may explain that lack of interest and moroseness are more common symptoms than sadness.

To better understand this phenomenon, researchers at Inserm Unit 1000 “Neuroimaging and Psychiatry”, led by Jean-Luc Martinot, in collaboration with a team from King’s College (London) have studied over 1,500 young people (at 14 years old and two years later) using magnetic resonance imaging (MRI) through the European study IMAGEN. Participants were split into three groups: one group with depression, a second group with isolated symptoms of depression with no actual diagnosis and finally, a group of healthy subjects

Each participant had to carry out a task where the brain’s reward response could be assessed (winning points in a game). The results of the simulated MRI confirms the scientists’ hypothesis—that adolescents with depression or occasional symptoms of depression have reduced activity in a specific area of the brain, the ventral striatum, which is involved in the reward circuit. It is significant that the response in this region is even weaker than the depressed person’s lack of interest.

The low activity in this region detected in healthy adolescents at 14 years old is correlated with the onset of depression or symptoms of depression at age 16”, explains Jean-Luc Martinot, Research Director at Inserm.

This study shows that impaired reward circuitry function is a factor that renders adolescents vulnerable to depression. The detection of symptoms involving loss of interest in adolescents and taking them into account in the early stages may help predict the onset of the disease or relapse and, as such, enable targeted early intervention well in advance.

Coffee colour…

Birthmarks, café au lait spots—although usually harmless (over 10% of the population has one or two), the presence of more than 5 of them in a child can conceal a hereditary disease, neurofibromatosis type 1 (NF1).

This is one of the most common genetic diseases (affecting 1 in 3,000 individuals). Until now, the molecular mechanisms associated with altered skin pigmentation were poorly understood, particularly since few appropriate models have been developed in the laboratory.

Inserm researchers at I-Stem (Institute for Stem Cell Therapy and Exploration of Monogenic diseases) have developed a model reproducing in vitro the hyperpigmentation associated with type 1 neurofibromatosis  from embryonic stem cells carrying the mutation responsible for this disease[1].

By establishing a protocol for differentiating these cells into melanocytes (the cells in the skin that can produce the melanin that gives it colour), the researchers were able to find the cause of generalised hyperpigmentation and formation of “café au lait” spots. The loss of neurofibromin expression in these NF1 melanocytes leads to a cascade of dysregulation. First, dysregulation of the AMPc and ERK signalling pathways, followed by dysregulation of the transcription factor MITF, and ultimately, increased expression of the enzymes involved in melanin production.

To correct this, the researchers used pharmacological inhibitors specific for these different signalling pathways, and were able to restore the cells to normal pigmentation levels.

This hyperpigmentation defect could be corrected by single small molecules (such as kojic acid, which is already contained in skin creams or lotions for lightening the skin), demonstrating the potential of pluripotent stem cells as a model for the study of pigmentation disorders.

The researchers now plan to identify and characterise the molecular mechanisms associated with other pigmentation-related conditions to find new therapeutic strategies, which are currently based on the use of mouse models, in which the melanocytes do not have the same location as in humans.

[1] These stem cells represent an unlimited source of cells that can theoretically differentiate into all the types of cells in the body, thus making it possible to demonstrate pathological phenotypes.

Melanocytes (cells producting melanin) © Inserm/Baldeschi, Christine

An atlas of human brain connections !

One of the major challenges of modern neuroscience is to define the complex pattern of neural connections that underlie cognition and behaviour. Brain connections have been investigated extensively in many animal species, including monkeys. Until recently, however, we have been unable to verify their existence in humans or identify possible tracts that are unique to human brain.

The Atlas of Human Brain Connections realized by Marco Catani and Michel Thiebaut de Schotten, researcher at Inserm, capitalizes on novel diffusion MRI tractography methods to provide a comprehensive overview of connections derived from virtual in vivo tractography dissections of the human brain.

It starts with an historical overview of the giant steps taken in neuroanatomy, from its birth more than 2000 years ago, to contemporary neuroimaging insights. Next, detailed descriptions of the major white matter connections, their function, and associated clinical syndromes are dealt with in detail. The composite maps of the atlas are an excellent anatomical resource for teaching, clinical, and research purposes. By reviewing both the basic principles of neuroanatomy, its historical roots, and its modern achievements in the field of DTI tractography, the book constitutes a valuable reference work for experienced clinicians and researchers working in the field of neurology, psychiatry, neurosurgery, and neuroradiology.

L’atlas offre un aperçu historique des grandes découvertes en neuroanatomie, depuis sa naissance il y a plus de 2000 ans, jusqu’aux récentes avancées scientifiques. Il décrit des connexions importantes de la substance blanche, leur fonction, et leurs syndromes cliniques associés. Les “cartes composites” de l’atlas sont une source d’information qui peut être utilisée pour l’enseignement anatomique, clinique et à des fins de recherche.

En examinant à la fois les principes de base de la neuroanatomie, ses racines historiques, et ses récentes découvertes dans le domaine de la tractographie des IRM DWI, ce livre est un ouvrage de référence pour les cliniciens expérimentés et les chercheurs travaillant dans le domaine de la neurologie, la psychiatrie, la neurochirurgie, la neuroradiologie et la neuropsychologie.