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On July 13, 2017, the journal Lancet Neurology published the results of a gene therapy trial conducted in four children with Sanfilippo type B syndrome (also known as MPS IIIB). This trial is the achievement of a two-decade partnership with financial support of AFM-Téléthon and the cooperation of the charity “Vaincre les Maladies Lysosomales” (VML). After monitoring of the treated children for 30 months, Dr. Jean-Michel Heard, from the Institut Pasteur and Inserm, and Professors Marc Tardieu and Michel Zérah, from the Paris public hospital administration (AP-HP) and the Paris-Sud and Paris Descartes Universities, conclude that the treatment was well tolerated and associated with neurocognitive benefits for the patients.

Sanfilippo syndrome is a rare genetic disease which affects approximately one in every 100,000 children. It alters brain development after birth and leads to brain degeneration several years later. The first symptoms of the disease are hyperactivity and delayed cognitive acquisition, which are usually noticed when children are around two-years old. A genetic anomaly prevents the production of an enzyme needed to breaking down mucopolysaccharides. Mucopolysaccharides are large macromolecules that help the neurons develop effective connections in young children during learning. Incomplete degradation and accumulation are toxic for brain cells. The disease progressively leads to a state of severe and multiple impairments and to premature death within periods of 5 to 10 years.

The challenge to treat Sanfilippo syndrome lies in the design of a method to supply the missing enzyme to the brain as early as possible after birth.  The therapeutic trial conducted by the Institut Pasteur at the Bicêtre Hospital (AP-HP) used gene therapy for that purpose. A gene therapy vector (AAV2/5) capable of inducing the production of the missing enzyme by brain cells was injected at several sites in the brain and cerebellum of affected children. The specific aim of this phase I/II trial was the assessment of tolerance to the surgical procedure and to the candidate drug delivered by gene therapy.

The clinical study initiated in 2013 was preceded by more than ten years of preclinical studies in animals naturally affected by the disease. The researchers administered the treatment for the first time to four children aged between 1.5 and 4 years (20, 26, 30, and 53 months). No particular clinical, radiological or biological side effects associated with the treatment were observed within 30 months of administration, indicating that it was well tolerated.

Within one month of treatment and throughout the 30 months of the trial, researchers detected the previously missing enzyme in the cerebrospinal fluid of the four treated children. Moreover, very careful and regular neurocognitive monitoring revealed positive impact on cognitive acquisition and behavioral development, which were more pronounced in the youngest treated child.

The encouraging findings of this phase I/II clinical trial suggest that treatment could be proposed to patients with Sanfilippo syndrome in the future.  To reach that goal, the next step would consist in a large and multicentric phase III clinical trial, if an appropriate partner is found.

A team of young researchers under the supervision of Guillaume Montagnac, Inserm research leader at Gustave Roussy, in collaboration with the Institut Curie and the Institut de Myologie (Myology Institute), has discovered a new mechanism which facilitates cell migration. On the surface of its membrane, the cell develops multiple small hooks which help it to attach to fibres outside the cell and move along them. This action helps us to understand better how a cell escapes from the tumour mass and moves around the body to form a new focus. This research is published in the 16^th June issue of the American journal Science.

Cell migration is a normal process which is essential to life. In oncology it is involved in the formation of new metastases.

“Up till the present, we knew that the cell relied on certain structures to anchor itself within its environment. We have now identified new cell structures known as ‘clathrin-coated pits’, already known to be important for other cell functions. The cancer cell uses them as hooks to attach to other structures in order to move around, These novel structures underlie some 50% of cell adhesion to surrounding structures,” declared  Guillaume Montagnac, Leader of the ATIP-Avenir team, attached to Inserm Unit 1170, “Normal and abnormal haematopoiesis”, at Gustave Roussy.  

Recognised in 1964, these clathrin pits are small invaginations of the cell membrane which allow it to renew itself or to help molecules to enter the cells. The cell uses them particularly to supply itself with nutritional material (iron, cholesterol, etc.).

Using fluorescence methods, the researchers succeeded in demonstrating with an aggressive human breast cancer line, known for its marked propensity to metastasise, that the clathrin pits adhere to collagen fibres and surround them. The pit squeezes the fibre, so strengthening its hold and allowing it to move.  

“Our Gustave Roussy team is one of the few with an interest in cell membrane dynamics when the cell is placed in 3D matrices under conditions close to normal ones. By studying these clathrin pits in 3D we were able to see the phenomenon when we were not expecting it,” concluded Guillaume Montagnac.

A breast cancer cell with actin (engine of migration) in red, the clathrin pits (cell hooks) in green and collagen fibres in blue

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It is known that IGF-1 (insulin-like growth factor) is needed for development and also plays a role throughout the body’s life. Previously, the team led by Martin Holzenberger (Inserm/UPMC Unit 938, Saint-Antoine Research Center) has shown that this hormone is involved in longevity and in Alzheimer’s disease. The team has recently conducted further research on IGF-1 and the response of neurons to this kind of neurodegeneration. These new results have been published in Brain.

Secreted by the liver and stimulated by growth hormone, IGF-1 (insulin-like growth factor) is able to stimulate the growth and maturation of bone and other organs, regulate energy metabolism, and control the aging of the whole body. In its previous work, the Holzenberger team had demonstrated in mice that when the number of IGF-1 receptors present in the neurons was reduced by genetic mutation, the level of IGF-1 in the blood decreased and the mice had a longer lifespan.

In this new study, published in the journal Brain, Martin Holzenberger and Saba Aïd have conducted further research on IGF and Alzheimer-type neurodegeneration. These researchers first show that inhibiting IGF-1 receptors in the neurons of mice led to a much later presentation in their brains of the signs of lesions typical of Alzheimer’s disease, in particular amyloid plaques and neuroinflammation. Reduced cognitive impairment was also observed in the same mice. Importantly, the team has shown that suppression of the IGF receptor leads to a series of neuroprotective effects. This confirms their previous results concerning prolonged lifespan.

This new study reveals a self-defense system used by the neurons when they suffer the kind of harmful attack typical of Alzheimer’s disease. In fact, the gene families activated in Alzheimer neurons and in the neurons deprived of the IGF-1 receptor are essentially the same. This suggests that, in the early stages of the disorder, a neuron faced with an Alzheimer-type disease is able to instigate a process of self-defense of its own accord (this is called an endogenous response). This endogenous response is not however sufficient over the long-term in a brain affected by Alzheimer’s, and effective protection against the disease requires total suppression of IGF-1 receptors in the neurons. It is not yet known at what point this neuronal response ceases to be effective against the disease.

These results enable a better understanding of the mechanisms of Alzheimer-type neurodegeneration, a disease that affects nearly one million people in France. This work is crucial, suggesting a paradigm shift concerning the role of IGF-1 in the progression of age-related neurodegenerative diseases: it is not stimulation, but rather long-term blocking of IGF signaling that would improve neuronal function and neuroprotection.

Ultimately, this work will lead to the development of new therapeutic and preventive targets in the fight against Alzheimer’s disease. However, the researchers emphasize that there is still a long way to go. “We cannot inhibit the IGF-1 receptor throughout the entire body because this hormone is essential for other cells. However, specifically targeting the neurons is a possibility. In any case, we have to better understand how to benefit from the good effects of IGF while preventing its less beneficial effects. “, concludes Martin Holzenberger.

A study conducted by Inserm researchers at the Research Institute for Environmental and Occupational Health (Irset)[1] has shown that natural selection has “purged” our bodies of many of the traces of our ancient Neanderthal and Denisovan cousins in the genes responsible for the genetic mixing essential to reproduction. The researchers have shown that the genes expressed during meiosis in the cells that produce gametes (reproductive cells) are strongly deficient in genetic variations of Neanderthal origin that were the result of the interbreeding between Homo sapiens and Homo neanderthalensis. These results have been published in Molecular Biology and Evolution.

For decades, a question has preoccupied paleontologists regarding our now-extinct cousins, the Neanderthals and Denisovans:  what was the nature of the interactions between modern humans (Homo sapiens) and the other species of the Homo genus ?

Well, hundreds of thousands of years ago, a succession of human migrations from Africa to the other continents led to the coexistence in Eurasia of Homo sapiens with various other now-extinct species of the Homo genus. In 2014, the sequencing of a Neanderthal genome was made possible by the discovery of bone fragments containing DNA. With the very recent emergence of paleogenomics, it has been established that 1 to 3% of the genome of present-day Eurasians is inherited from the Neanderthals, whereas 3 to 6% of that of Oceanians is inherited from other ancestral cousins, the Denisovans. The women and men that populate our planet today are the result of many interbreeding events that have enabled human populations to expand thanks to the acquisition of characteristics favorable to climatic and environmental adaptations.

However, a surprising particularity recently came to light: the genetic variations inherited from interbreeding with these extinct species are not evenly distributed on the chromosomes. As such, Prof.  David Reich’s team demonstrated that these “archaic” genetic variations are present only to a very minor extent on the genes expressed specifically in the testis of modern humans.

Hence the key question studied by the researchers in Rennes: within the testis and ovary, to which specific functions are these genes, deficient in Neanderthal and Denisovan genetic variations, assigned ?

To answer that question, researchers from Inserm compared the genes present in the different cell types of the testis (germ line cells, Sertoli cells, Leydig cells, etc.).

The results obtained show that it is only those genes expressed specifically during meiosis, the process responsible for genetic mixing, that are highly deficient in ancestral alleles of Neanderthal and Denisovan origin. The conclusions were the same when the germ cells present in human fetal ovaries were studied. Since meiosis is a unique and fundamental process of spermatogenesis and oogenesis, natural selection has therefore “purged” our gene pool of the genetic variations that could have adversely affected its progression and thus prove harmful to the continuation of our species.

For the study’s coordinators Frédéric Chalmel and Bernard Jégou, this shows that “while interbreeding between modern humans and these extinct hominins has enabled us to acquire new adaptive traits important for our survival, it probably had a negative impact on the fertility of the initial hybrids. That is certainly why the genes involved in meiosis, a particularly sensitive biological process, have been purged of genetically archaic variations.  This is the first paleo-fertility study and it is likely to reveal evolutionary processes involved in certain present-day cases of infertility.”

[1]  Research Institute for Environmental and Occupational Health; Inserm; EHESP School of Public Health, Université de Rennes 1.

Rénald Delanoue, Inserm Researcher, and his colleagues at the Institute of Biology Valrose in Nice (Inserm-CNRS-Université Côte d’Azur) have identified the missing links in the process that regulates the size of an organism based on the richness of its diet. Their research was conducted on Drosophila, an insect that seems very distant from humans, but the study of which has nonetheless enabled many advances in biomedical research. This work is published in the 30 September 2016 issue of the journal Science.

The size of an organism depends on its nutrient intake during development. In the event of a nutrient deficiency during this period, animals modify their growth and become adults of small size, while retaining the correct proportions. This coupling between nutrition and growth involves hormones from the insulin family and IGFs (insulin growth factors); however, the molecular mechanisms that govern this regulation are still not well understood.

Work done by Inserm researchers at the Institute of Biology Valrose (Inserm-CNRS-UCA) has enabled the identification of the substances on which this coupling is based at molecular level in the fruit fly (Drosophila melanogaster). Despite 700 million years of evolutionary divergence, this insect is a relevant model for biomedical research, because it possesses the same physiological processes as mammals.

For example, it is interesting to know that the fat body in Drosophila fulfils the same roles as the liver and adipose tissues in humans. The neurosecretory insulin producing cells (IPCs) are located in the larval brain of the insect, and correspond functionally to the pancreatic β-cells in humans.

Using the Drosophila model, these researchers have already shown that the coupling of nutrition and growth requires communication between these two organs (ndlr fat body and IPCs). Depending on the quantity of amino acids available in the diet, the fat body sends different signals to the brain. The IPCs are able to interpret these, and to secrete the appropriate amount of insulin. A low level of amino acids induces a reduction in insulin secretion and a slowing in growth, and vice versa.

It remained necessary to identify the nature of these remotely acting signals, and the IPC molecule capable of interpreting them to determine the quantity of insulin to be secreted. To do this, the researchers inhibited, one by one, the known receptors on IPCs, and identified the Methuselah receptor, inhibition of which blocks insulin secretion.

The Stunted protein, which binds to this receptor, was known, but had not been linked to the regulation of insulin secretion. And for a reason! This protein is usually found mainly inside the cells, and plays a role in ATP synthesis. It was therefore surprising to find it freely circulating in the haemolymph of the insect (the equivalent of the bloodstream). The researchers showed that the level of circulating Stunted varies with the quantity of amino acids present in the diet. Its suppression disrupts insulin secretion, and gives rise to adults of small size. Finally, they also demonstrated that this “signalling” function of Stunted in communication between two organs is a novel one, and independent of its function in ATP synthesis.

These results, although very fundamental, could nonetheless guide the study of the molecular circuits of certain diseases such as diabetes, obesity or some forms of cancer that depend on hormones and receptors from the same family as those described in Drosophila. Stunted proteins, which have been found on the surface of many cell types, could also play a signalling role in humans.

The fluorescent protein GFP (green) is expressed in insulin producing neurons, IPCs (dotted white lines). Secretion of Drosophila insulins (Dilp2, in red) is regulated in these specialised neurons by the presence of the Methuselah receptor. The absence of this membrane protein in Mth- IPCs leads to blocking of insulin (Dilp2) secretion and its accumulation in IPCs (bottom row), compared with the control (top row).

(c) Rénald Delanoue/Inserm