Institut Imagine

Une nouvelle molécule pour corriger les défauts de croissance ?

Anonymous — Wed, 16 Jul 2025 08:28:51 +0000

A new molecule to correct growth defects? Anonymous (not verified) Wed, 07/16/2025 - 10:36

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« In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the fibroblast growth factor receptor 3 (FGFR3) receptor tyrosine kinase (TK) account for Achondroplasia » Laurence Legeai-Mallet, Inserm Research Director at Institut Imagine (Inserm, AP-HP, Université Paris Cité), recently explained to Cahiers de l'Inserm. Achondroplasia (ACH), the most common form of dwarfism, and hypochondroplasia (HCH), a less severe form, are both the consequence of gain-of-function mutations (hyperactive protein) in the FGFR3 gene. After identifying the responsible gene, the team developed cell and animal models to better understand these diseases, and test the efficacy of various therapeutic molecules.

Several treatments are currently being developed to reduce these growth defects. After vosoritide (marketed in 2021 under the name Voxzogo) and infigratinib (currently in phase 3 trials), the team has recently evaluated the efficacy of a new molecule, TYRA-300, synthesized by the company Tyra Biosciences. This small molecule, a tyrosine kinase inhibitor specifically inhibiting FGFR3 (and not other members of the FGFR family), could be more effective, and with a wider therapeutic window, than non-selective FGFR inhibitors.

The efficacy of TYRA-300 was evaluated in ACH and HCH mice, for which infigratinib has already shown efficacy. In an article recently published in JCI Insight, Laurence Legeai-Mallet's team shows that after 2 weeks of daily treatment for ACH mice and 3 weeks of daily treatment for HCH mice, TYRA-300 increases total growth velocity and long bone growth. Skull shape and size were also improved; bone parameters of long bones, vertebrae and intervertebral disc architecture were also partially corrected, suggesting that the molecule has an effect on the entire musculoskeletal system.

The researchers also studied the ossification process over time and confirmed that cartilage cell proliferation and differentiation, as well as osteogenesis, were disrupted by Fgfr3 mutations. The team showed that TYRA-300 restores growth plate architecture by increasing cartilage cell proliferation and differentiation.

Overall, the current study demonstrates that TYRA-300 effectively promotes bone growth in two models of chondrodysplasia linked to FGFR3 mutations. TYRA-300 is therefore the first selective FGFR3 inhibitor to be evaluated in these models. In the future, TYRA-300 may offer a wider therapeutic window than the non-selective FGFR inhibitors currently in development. Taken together, these data justify the initiation of a clinical trial of TYRA-300 in children with ACH, HCH and potentially other FGFR3-related osteochondrodysplasias, in the hope of developing an effective, safe and universally accessible treatment.

Reference :

TYRA-300, an FGFR3-selective inhibitor, promotes bone growth in two FGFR3-driven models of chondrodysplasia

Starrett JH*, Lemoine C*, Guillo M* et al., JCI Insight, 2025

Corresponding author : Laurence Legeai-Mallet

https://doi.org/10.1172/jci.insight.189307

Accroche

Achondroplasia (ACH), the most common form of rhizomelic dwarfism, and hypochondroplasia (HCH), a less severe form, are both linked to gain-of-function mutations (hyperactive protein) in the FGFR3 (Fibroblast Growth Factor Receptor 3) gene. The activated receptor disrupts skeletal bone growth by affecting both chondrogenesis (cartilage tissue formation) and osteogenesis (bone formation and development), leading to significant shortening of long bones.
In this new study, Laurence Legeai-Mallet's team investigated TYRA-300, a potent and selective inhibitor of FGFR3. The scientists have evaluated this new therapeutic solution in mouse models of ACH and HCH. Treatment with TYRA-300 increased total growth and the length of long bones, and modified the shape of the skull. The results obtained show that TYRA-300 is effective, has no side effects and significantly improves bone growth. This new molecule represents a new promising treatment for patients with FGFR3 mutations.

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Jeanne Amiel and Laurence Legeai-Mallet

Projet InFlaMe : étude des interactions entre le virus et l'hôte et les stratégies de défense pour concevoir de nouvelles thérapies contre les flavivirus

Anonymous — Tue, 08 Jul 2025 14:42:27 +0000

InFlaMe project: addressing virus-host interactions and defense strategies to design new therapeutics against flaviviruses Anonymous (not verified) Tue, 07/08/2025 - 16:46

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Flaviviruses, such as Dengue virus (DENV) and West Nile virus (WNW), are viruses spread by mosquitoes that cause serious illnesses in humans and animals. They are becoming increasingly common in Europe, with both imported and local cases on the rise due to urban growth, climate change, and global travel. Consequently, almost half the world’s population is at risk, and the economic impact is huge ($12 billion per year). Currently, only a few vaccines with limited effectiveness on DENV and WNW exist, and no specific treatment for humans is available. Therefore, better understanding of the immune response and improving diagnosis is crucial to controlling these viruses. InFlaMe project aims to help the EU better prepare for, and respond to the outbreaks of DENV and WNV. This four-year project focuses on three main areas: understanding why some people get more seriously ill compared to others when infected, developing new treatments, particularly ones that can block how the viruses interact with the human body, and tracking the spread of the viruses in both people and animals using a "One Health" approach, which looks at human, animal, and environmental health together. Based on these outcomes, the project ultimately aims to strengthen the EU's ability to fight DENV and WNV epidemic and pandemic threats and develop effective emergency plans.

InFlaMe consortium, led by the Professor Fausto Baldanti from the Fondazione IRCCS Policlinico San Matteo in Pavia, Italy, unites partners from Italy (Fondazione Istituto Nazionale di Genetica Molecolare INGM, Universita Degli Studi di Firenze, Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna Bruno Ubertini, Consiglio Nazionale delle Ricerche), France (Institut Imagine, Institut Pasteur), Austria (Medizinische Universitaet Wien), Czechia (Masarykova Univerzita), and Spain (Asociacion Centro De Investigacion Cooperativa En Biociencias) that bring unparallel expertise in diagnosis of flavivirus infections in humans and animals, host-pathogen interactions and drug discovery.

The consortium will enable the EU to work out an integrated contingency plan (pandemic preparedness) that will go beyond individual national emergencies.

The official start of the project, set for the 1^st of January 2025, was marked with a first in-person meeting of the consortium members, with the participation of the Project Officer from European Health and Digital Executive Agency (HaDEA) and members of the Advisory Board, at the Palazzo Bellisomi-Vistarino in Pavia, Italy, on the 4^th and 5^th of February 2025.The meeting provided an excellent opportunity for each partner of the consortium to introduce their teams, expertise, and roles within the project, as well as to engage in detailed discussion on the objectives and tasks for each work package and assess potential risks, along with strategies for mitigation. In his welcoming speech, the coordinator emphasized the consortium's responsibility to deliver results, highlighting their significance for the future, especially in light of recent outbreaks, as well as the importance of InFlaMe for policymakers in relation to the “One Health” approach.

The project website, which has recently been launched, will serve as a platform to inform and educate the citizens on the goals and milestones of the consortium in their effort to understand, fight, and prevent future DNV and WNV pandemics and epidemics.

In parallel, study and consortium news will also be continuously shared through the project’s LinkedIn page.

Read the full press release

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From the 1st of January 2025, Institut Imagine (Inserm, AP-HP, Université Paris Cité) is participating in the transnational InFlaMe project, funded through Horizon Europe’s ‘Pandemic preparedness and response: Host-pathogen interactions of infectious diseases with epidemic potential’ call.

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Jean-Laurent Casanova

Une nouvelle MEDopathie par mutations bialléliques de MED16

jordane.galera@institutimagine.org — Wed, 18 Jun 2025 15:38:55 +0000

A new MEDopathy caused by biallelic mutations of MED16 jordane.galera… Wed, 06/18/2025 - 17:41

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The sequencing of the genomes of a brother and sister with several developmental anomalies (growth retardation, motor retardation, intellectual disability and cardiac, limb and craniofacial malformations) identified a biallelic mutation (on both chromosomes) in the MED16 gene. This gene encodes a subunit of the Mediator complex, a multi-protein complex that regulates transcription, the first stage of gene expression during which DNA is “copied” into RNA. Pathogenic variants of other Mediator subunits, already identified in human diseases, generally lead to neurodevelopmental or neurodegenerative disorders that may be associated with malformations of other organs, and are grouped together under the term MEDopathies. A new study by the former “Embryology and Genetics of Malformations” laboratory at the Institut Imagine has described a novel rare congenital malformation syndrome: acrofacialdysostosis (craniofacial and limb malformation) with intellectual disability, resulting from biallelic mutations in the MED16 gene.

Using the GeneMatcher database, the team was able to identify a further 23 individuals from 17 families with biallelic MED16 mutations. This cohort of 25 individuals is reported by Charlotte Guillouet, a PhD student under the supervision of Chris Gordon and Jeanne Amiel in the “Embryology and Genetics of Malformations” laboratory at the Institut Imagine (Inserm, AP-HP, Université Paris Cité). In silico (computer simulation) and in vitro (test tube, laboratory) studies validated the pathogenicity of the vast majority of the MED16 variants.

Finally, two zebrafish lines in which the med16 gene is “switched off” show stunted growth and early mortality compared with “normal” fish or fish carrying the mutation on a single chromosome, thus confirming the important role of med16 during development.

This study, recently published in the American Journal of Human Genetics, describes a novel, rare autosomal recessive MEDopathy syndrome (the mutation must be present on both chromosomes for the disease to appear). It also confirms the importance of optimal functioning of the Mediator complex for brain development, and suggests a more specific role for certain subunits during development.

Reference :
Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations
C Guillouet et al., Am J Hum Genet, 2025
Corresponding authors : Charlotte Guillouet, Jeanne Amiel and Chris Gordon
DOI : 10.1016/j.ajhg.2025.02.016

Accroche

Members of the former “Embryology and Genetics of Malformations” laboratory at Institut Imagine have sequenced the genome of a brother and sister with an undiagnosed acrofacialdysostosis (craniofacial and limb malformations) and intellectual disability. The team identified variants of the MED16 gene. This gene encodes a subunit of the Mediator multiprotein complex, which regulates the transcription of DNA into RNA. By sharing genomic data, the researchers identified a cohort of 25 individuals carrying biallelic variants of MED16 and confirmed the causality of this gene. The results, recently published in the American Journal of Human Genetics, show the impact of missense variants on protein conformation and cellular localization. Finally, by invalidating this gene in zebrafish, they observed a growth defect and early death of larval fish, confirming the essential role of med16 in development. This study thus describes a new MEDopathy and the major role of the MED16 gene in craniofacial, limb, heart and central nervous system development.

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Drépanocytose : l’efficacité de la thérapie génique dépend du degré d’inflammation de l’hôte

jordane.galera@institutimagine.org — Thu, 12 Jun 2025 12:38:44 +0000

Sickle cell disease: gene therapy efficacy depends on degree of host inflammation jordane.galera… Thu, 06/12/2025 - 14:48

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The results, recently published in Nature Communications, indicate that this new therapy is safe, with no side effects in the years following transplantation. However, its efficacy is variable and depends not only on the number of HSCs transplanted, but also on the host's inflammatory state and its impact on the biology of its stem cells. These data show that it is possible to assess the quality of these cells prior to implantation, thanks to the use of new single-cell analysis technologies enabling fine characterization of this rare population of cells. This study represents a major step forward in the development of a safe and effective gene therapy to treat sickle cell disease, the “most common of rare diseases”.

Sickle cell disease is a widespread genetic disorder in which a point mutation in the HBB gene affects the hemoglobin in red blood cells. This form of hemoglobin, known as sickle cell hemoglobin (HbS), accumulates in the red blood cells and causes them to become misshaped, taking on a sickle shape. These deformed red blood cells lead to anemia, painful seizures and an increased risk of infection. Although current treatments have greatly increased the life expectancy of affected patients, they are still limited.

Autologous (patient-derived) hematopoietic stem cells (HSC), which reside in the bone marrow and are the source of all blood cells, can be genetically modified before being retransplanted into patients: this protocol is a promising therapeutic option for patients who do not have a suitable donor.

This treatment has already been used in a clinical trial with patients suffering from β-thalassemia, another genetic hematological disease. Researchers at Institut Imagine (Inserm, AP-HP, Université Paris Cité) and the Biotherapy Department at Hôpital Necker-Enfants malades AP-HP have adapted the genetic vector developed in this trial for use in sickle cell gene therapy. This new vector, called DREPAGLOBE, enables the expression of “healthy” β-globin (the component of hemoglobin) and reduces the rate of sickle cell red blood cells by up to 50%.

Following production and validation of this therapeutic vector, a clinical trial was launched in November 2019 at Necker-Enfants malades hospital, to assess the safety and efficacy of therapy by transplantation of autologous HSCs modified with the DREPAGLOBE vector. The teams examined factors that may influence the uptake of genetically modified cells in sickle cell patients, and the efficacy of transplantation in this devastating disease.

The primary endpoint of the clinical trial was short-term safety, and the secondary endpoints were long-term efficacy and safety. After 18 to 36 months of follow-up, no treatment-related adverse events or signs of abnormal hematopoiesis were observed. However, despite a similar number of vector copies in the initial treatment, the frequency of “corrected” red blood cells and disease correction varied from patient to patient. Cellular analysis in patients with poor graft intake showed that these differences can almost certainly be explained by the host's degree of inflammation and its repercussions on the functionality of their HSCs. The researchers have thus characterized three criteria that must be met for gene therapy to be effective: the number of corrected and grafted HSCs, the level of inflammation and an absence of skewing in HSC differentiation. Thanks to these elements, a specific treatment will be proposed to patients in the new clinical trial currently in preparation (DREPAMIR trial).

The results of this trial, recently published in the prestigious scientific journal Nature Communications, confirm that this gene therapy based on DREPAGLOBE is safe and free of side effects in both the short and long term. However, its efficacy is variable and depends on the number of transplanted HSCs and their inflammatory state, assessed by gene activity, in relation to the host's biological characteristics. Although the response to treatment remains to be improved for certain patients, this study represents a major step forward in obtaining a safe and effective gene therapy to treat sickle cell disease, in a personalized manner and with proven long-term benefits.

Reference :
Severe inflammation and lineage skewing are associated with poor engraftment of engineered hematopoietic stem cells in patients with sickle cell disease
S Sobrino et al., Nat Commun., 2025
Corresponding author : Marina Cavazzana
DOI : 10.1038/s41467-025-58321-4

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Drépanocytose

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Sickle cell anemia is a hereditary genetic disease affecting red blood cells: a simple mutation results in the production of misshaped red blood cells known as sickle cells. Red blood cells are derived from hematopoietic stem cells (HSC), which are capable of multiplying very actively before becoming mature red blood cells. Correcting the mutation in these cells means that “normal” red blood cells can be produced, and the disease cured. To achieve this, researchers at Institut Imagine and the Biotherapy Department from Hôpital Necker-Enfants malades genetically modified HSCs from sickle cell patients in the laboratory, before reinfusing them. The patients were followed by the teams for 2 to 3 years to confirm the absence of side effects and the degree of efficacy of this gene therapy.

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Notch3, un nouvel acteur confirmé du développement et de l’asymétrie du coeur

jordane.galera@institutimagine.org — Wed, 04 Jun 2025 12:44:52 +0000

Notch3, a new player in heart development and asymmetry jordane.galera… Wed, 06/04/2025 - 14:48

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The left-right laterality of the embryo is essential for the formation of asymmetric visceral organs. Anomalies in the lateralization process lead to the heterotaxy syndrome, a severe condition including complex cardiac malformations that can be fatal. The mechanisms of symmetry breaking during embryonic development are now well established in the mouse : motile cilia present on the surface of embryonic cells, at the level of the “left-right organizer node”, generate a leftward fluid flow . This flow is detected by specific cells which, according to this signal, asymmetrically synthesize the Nodal left determinant in the embryo. Genetic alterations in node formation, cilia formation or Nodal signaling are thus associated with heterotaxy in mice and humans.

The heart is the first organ to undergo asymmetric morphogenesis in the embryo. Sigolène Meilhac, who heads the “Heart Morphogenesis” lab at Institut Imagine (Inserm, AP-HP, Université Paris Cité), and her team had already shown that in the absence of Nodal, asymmetries are present but reduced, and that the shape of the cardiac tube (the embryonic heart) is abnormal. This indicates that Nodal is not always necessary to initiate asymmetry, and that there are other asymmetry factors in addition to Nodal signaling.

In their work, recently published in PlosBiology, the researchers focused on asymmetric gene expression during embryonic development. By comparing left and right samples, they revealed that Notch3 is a novel gene enriched on the left side of the embryo. Notch3, a member of the Notch receptor family, is already known for its role in the formation of arterial smooth muscle, for example in the CADASIL syndrome, a genetic disease affecting small blood vessels in the brain. Sigolène Meilhac team has now shown that Notch3 is expressed in cardiac cells and co-expressed with Nodal. Single mutation of Notch3 does not cause heterotaxy, but does generate anomalies of the ventricle, aortic valve, cardiac septation and coronary artery. In contrast, Notch3 mutation worsens the phenotype of Nodal mutants, demonstrating its role as a modifier gene for laterality defects.

In a cohort of patients, the researchers also identified rare new variants of the NOTCH3 gene, associated with two types of cardiac anomalies : similar to those observed in Notch3 mutant mice, or similar to those observed in heterotaxy.

These results are therefore crucial in demonstrating two new roles for Notch3, both in heart development and in left-right laterality. In humans, NOTCH3 had so far been mainly associated with vascular anomalies (such as in the CADASIL syndrome mentioned above, or Sneddon syndrome) or neural anomalies, such as in the lateral meningocele syndrome, all rare diseases of genetic origin. However, rare patients with lateral meningocele syndrome also have cardiac anomalies, the origin of which remained enigmatic. The work of Sigolène Meilhac team shows that Notch3 mutant mice have the same cardiac defects as these patients. This work overall extends the spectrum of malformations associated with NOTCH3 in patients, and provides novel insights on the mechanisms of heart development and lateralization.

Reference :
Notch3 is an asymmetric gene and a modifier of heart looping defects in Nodal mouse mutants
Tobias Holm Bønnelykke et al., Plos Biology, 2025
https://doi.org/10.1371/journal.pbio.3002598
Corresponding author : Sigolène Meilhac

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Accroche

The NODAL protein, from the TGFbeta family, is a major left determinant required during embryogenesis for the asymmetric development of visceral organs, including the heart. However, when this signaling is absent, organ asymmetry is not completely abrogated, indicating that there are other factors regulating left-right laterality. The lab of “Heart Morphogenesis” at Institut Imagine has developed a specific transcriptomic approach to search for genes expressed asymmetrically in embryonic heart cells. They identified Notch3 as a novel left-enriched gene. They also demonstrated that Nodal amplifies the asymmetric expression of Notch3. The function of Notch3 was discovered in mice with a Notch3 gene mutation : it is important for heart septation and aortic valve formation, in addition to its known role in coronary artery formation. Researchers also show that Notch3 acts as a genetic modifier of the cardiac loop (the embryonic heart) in Nodal mutants, i.e. laterality defects. In a cohort of patients, they identified rare NOTCH3 variants associated with cardiac septation and aortic valve defects or with laterality defects. These observations in mice and humans confirm a new role for Notch3 in congenital heart defects and laterality defects.

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Précision du rôle de la kinase IKKα dans le fonctionnement de la voie de l'inflammation NF-κB

Anonymous — Fri, 11 Apr 2025 08:20:51 +0000

Clarifying the role of IKKα kinase in the function of the NF-κB inflammation pathway Anonymous (not verified) Fri, 04/11/2025 - 11:20

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A signaling pathway is a series of steps, initiated by a stimulus, involving several molecules within a biological cell. The NF-κB pathway is a key player in immune and inflammatory responses. It can be activated by two different pathways:

The canonical pathway: which activates very rapidly and enables rapid reprogramming of immune cells in the face of an antigen or aggression.
The non-canonical pathway: activates more slowly, thanks to more specific stimulation, and has a more restricted role. It is particularly important for antibody-controlled immunity.

This NF-κB signaling pathway requires the activation of kinases, “switch” proteins that regulate numerous intracellular processes, namely IKKα (studied here) and IKKβ, both encoded by the CHUK gene. It was initially considered that IKKα had a key role in activating the non-canonical pathway, but that it was not required for the activation of the canonical pathway, itself mostly regulated by IKKβ.

Quentin Riller, together with Frédéric Rieux-Laucat, director of the “Immunogenetics of Pediatric Autoimmune Diseases” laboratory at the Institut Imagine (Inserm, AP-HP, Université Paris Cité), have focused on a patient suffering from syndromic immunodeficiency and various immune dysregulations. In an initial study by a Dutch research team, a heterozygous mutation (present on only one of the alleles) of the CHUK gene had already been identified in this patient, without being functionally studied.

In the patient's cells, the Institut Imagine researchers observed a significant alteration in the non-canonical NF-κB pathway. Even more surprisingly, they also observed partial defects in the canonical pathway; which was not supposed to be regulated by IKKα. The researchers then identified a second heterozygous mutation in this gene, in the other allele. The researchers thus describe for the first time composite heterozygous variants in the kinase domain of IKKα responsible for immune deficiency.

Furthermore, reintroduction of the CHUK gene in its unmutated form restores activation of the NF-κB non-canonical pathway. This means that the correct production of IKKα can restore the proper functioning of the non-canonical pathway, raising the prospect of therapeutic leads. These results, published in Journal of Experimental Medicine, call into question the origin of the patient's disease, which would therefore no longer be linked to an IKKα mutation but to the cumulative effect of the two mutations. This underscores the need to analyze and understand the impact of each mutation, in order to establish the most accurate diagnosis possible in the case of a genetic disease. Finally, since a defect in IKKα caused the canonical pathway to vary, this study confirms that there is an interaction between the canonical and non-canonical pathways. This then changes the idea we had of the role of IKKα and broadens our understanding of NF-κB pathway deficiencies.

This study not only broadened our knowledge of IKKα and the NF-κB pathway, but also highlighted the importance of detailed analysis of patients' genomes. In the future, these researchers would like to create a reference cohort on the IKKα gene, as already exists for other genes. Cases of IKKα mutation, such as those studied, remain very rare, however, as they are probably not very viable; nevertheless, the establishment of such a cohort would further enhance our understanding of the functioning of the NF-κB pathway, involved in many other physiological mechanisms and pathologies.

Reference :

Article title: Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans.

1st author et al, JExpMed, 2025

Corresponding author : Quentin Riller and Frédéric Rieux-Laucat

DOI : 10.1084/jem.20240843.

Accroche

A signaling pathway is a series of steps, initiated by a stimulus, involving several molecules within a biological cell. These pathways are crucial for coordinating the growth, regulation and function of cells and tissues. If signaling between or within cells is deregulated, inappropriate cellular responses can lead to cancer or other diseases such as autoimmune diseases or, conversely, immune deficiencies. The NF-κB signaling pathway is involved in our immune and inflammatory responses. It can be activated in two different ways: the canonical pathway (activated rapidly by numerous stimuli) and the non-canonical pathway (activated later by more restricted stimuli). Researchers from the “Immunogenetics of Pediatric Autoimmune Diseases” laboratory at Institut Imagine looked at a patient with hypogammaglobulinemia, recurrent lung infections and Hay-Wells syndrome, who carried two mutations in the CHUK gene (one on each allele) encoding the IKKα protein.

Their results, recently published in the Journal of Experimental Medicine, showed that these two mutations in the CHUK gene altered activation of the non-canonical NF-κB pathway, but also to a lesser extent the canonical pathway, confirming a crucial role for IKKα in both pathways. These results clarify our understanding of the functioning of the NF-κB pathway, involved in numerous biological mechanisms such as intercellular communication, innate and adaptive immune response and inflammatory response. They also shed light on the role of IKKα in this signaling pathway. This gene is still little studied, as highly deleterious mutations in IKKα seem to drastically affect development. The identification of this new mutation therefore represents a breakthrough in the diagnosis of children with symptoms similar to those of the patient.

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Frédéric Rieux-Laucat

Des interventions pédagogiques bénéfiques aux collégiens souffrant de difficultés d’apprentissages

Anonymous — Tue, 08 Apr 2025 06:19:28 +0000

Pedagogical interventions to help schoolchildren with learning difficulties Anonymous (not verified) Tue, 04/08/2025 - 08:26

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Specific Language and Learning Disorders (SLLD), now classified as a neurodevelopmental disorder, affect at least 8% of school-age children. As such, they constitute a worldwide educational and public health problem. In France, with a steady decline in middle-schoolers' math and writing levels since 2014, they are a particularly worrying issue. Difficult to categorize due to their heterogeneity, they generally correspond to learning difficulties, which can be identified by a standardized reading (fluency and comprehension), spelling and math test at the start of the school year.

Pioneering educational prevention programs in the USA have set themselves the goal of identifying at-risk or struggling students, and responding to their needs with evidence-based practice. Known as Response-To-Intervention (RTI), this program proposes a 3-stage pedagogy based on students' needs: stage 1 (whole-class teaching), stage 2 (complementary interventions for students in difficulty) and stage 3 in the event of persistent difficulties. In France, national assessments have been introduced to identify students requiring assistance at level 2. The Haute Autorité de Santé guide recognizes the preventive role of pedagogical interventions and describes the management of level 3.

Prof. Arnold Munnich (Institut Imagine, Inserm, AP-HP, Université Paris Cité) and Dr. Catherine Billard (Association pour la Recherche sur les Troubles des Apprentissages, ARTA) and their teams, with the support of ORT France, are evaluating the impact of small-group teaching interventions, compared with no intervention, in a sample of 6th and 5th graders with learning difficulties in French and/or math, over the course of 2021 and 2022. Unlike the majority of reported interventions, this study targeted pupils with learning difficulties at an advanced stage of their schooling, including pupils corresponding to the criteria for SLLD.

The protocol was drawn up and supervised by a multidisciplinary research team comprising a neuropediatrician, a neuropsychologist, a speech therapist and a statistical methodologist, in collaboration with the middle school's teaching team trained in typical and atypical learning.

The results of the study, just published in the journal Neuropsychiatrie de l'Enfance et de l'Adolescence (Neuropsychiatry of Childhood and Adolescence), clearly show the benefits, in addition to the regular school program, of small-group educational interventions targeting deficits in French and/or mathematics. The main benefits concern reading comprehension, numbering, addition and subtraction. Deficits in spelling and problem-solving are also reduced, though not to the level of the norm. While not all students caught up, dyslexics also benefited from French interventions targeting reading comprehension, as well as mathematical skills with math interventions. The persistence at a distance of the beneficial effect of all types of intervention confirms the positive impact of the program as a whole. This observation, which needs to be confirmed by other, larger and more robust studies, also underlines the fact that certain learning difficulties can be effectively reversed when teachers or coaches are trained in these pedagogical interventions.

This study constitutes an initial pilot experiment, essential for validating the choices of interventions in French and maths. The project is currently being extended by the teaching teams of the experimental middle school, using the compulsory National Assessments to identify students in difficulty, as well as a controlled observational project in the second year at the same school. Further, broader research in other contexts is required before the deployment of RAIs, which can only be gradual and carefully considered. As Caroline Viriot-Goedel, Professor of Education, points out : “While North American researchers and decision-makers continue to work on improving RAI in their schools, it is clear that the implementation of RAI in French schools will require in-depth reflection on the conditions for successful deployment in the French context”.

The study, carried out in schools belonging to the ORT France network, confirms that, if left unchecked, the deficits become more pronounced as the child progresses through secondary school : this finding argues strongly in favor of targeted remedial programs for learning difficulties, and of training teachers to provide these interventions.

Reference :

Impact of pedagogical interventions on written language or math learning difficulties in middle schoolers : a nonrandomized controlled study. C Billard et al., Neuropsychiatrie de l'Enfance et de l'Adolescence, 2025

DOI : https://doi.org/10.1016/j.neurenf.2025.02.003

Corresponding authors: Catherine Billard and Arnold Munnich (Institut Imagine, UMR 1163)

Accroche

Learning difficulties are a global educational and public health issue, particularly worrying in France, with a steady decline in middle school students' math and writing levels observed since 2014.
A study involving nearly 200 students from the middle schools of ORT France, a network of general, technical and vocational education establishments under contract with the French state, has just confirmed the beneficial impact of educational interventions targeting deficits in French and/or mathematics: the skills essential for the future of middle school students improved, even normalized, immediately after intervention and at a distance.
Although larger trials are needed to corroborate them, these results underline the value of pedagogical interventions by trained teachers to remedy learning difficulties in middle school. This finding argues in favor of setting up large-scale programs to remedy the learning difficulties observed in French children.

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Amélioration de la réparation osseuse grâce à des antagonistes des FGFRs dans un modèle d’hypochondroplasie

Anonymous — Fri, 04 Apr 2025 12:01:10 +0000

Enhanced bone repair with FGFR antagonists in a model of hypochondroplasia Anonymous (not verified) Fri, 04/04/2025 - 14:10

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Maxillofacial surgeon Dr. Anne Morice, under the supervision of Dr. Laurence Legeai-Mallet (Institut Imagine, Inserm, AP-HP, Université Paris Cité) recently studied mandibular bone repair in a mouse model of hypochondroplasia. Anne Morice's work has shown that HCH mice exhibit defective mandibular repair, characterized by poor bone mineralization, impaired cartilage cell differentiation and pseudarthrosis (lack of consolidation of bone fractures). The team also showed in a mouse model of Crouzon, a form of syndromic craniosynostosis (premature fusion of cranial sutures) linked to a FGFR2 mutation, that bone repair was conversely accompanied by excessively high bone mineralization in fractured bone areas.

The team then explored the potential of FGFR3 antagonists, which block the action of the FGFR3 receptor overactivated by the mutation, in an attempt to restore defective mandibular bone repair. Two FGFR3 antagonist molecules were tested during bone repair in this mouse model: infigratinib and vosoritide, two treatments administered to patients with achondroplasia (a more severe form of dwarfism also linked to a mutation in the FGFR3 gene) to increase bone growth.

Infigratinib or vosoritide administered during bone repair are highly effective, restoring a normal bone repair process in HCH mice. These treatments enhanced bone formation and mineralization of bone repair calluses by blocking FGFR3 overactivity. This finding highlights the critical role of FGFR3 in regulating bone repair, and suggests that FGFR antagonists could become a transformative therapeutic approach for treating bone repair defects associated with FGFR3 mutations.

Laurence Legeai-Mallet explains: “Our results highlight the crucial role of FGFR3 in bone repair processes. The beneficial effect of FGFR antagonists in our mice models provides a compelling argument for the development of targeted therapies to treat skeletal defects in patients with FGFR3-related diseases.”

The use of FGFR antagonists could revolutionize the treatment of defects in bone consolidation after fractures or bone surgery, as well as the treatment of craniofacial anomalies in patients with osteochondrodysplasias.

Anne Morice's recent work has been published in the scientific journal Bone Research.

This project is supported by the AXA Mutuals' Philanthropy Department as part of the Head and Heart Chair at Institut Imagine.

Reference:

FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia

Morice et al, Bone Research, 2025

DOI 10.1038/s41413-024-00385-x

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Hypochondroplasia (HCH) belongs to the group of osteochondrodysplasias, genetic disorders that impair bone development and formation, thereby affecting growth. HCH is a rare form of dwarfism, linked to so-called “gain-of-function” mutations in the FGFR3 (Fibroblast Growth Factor Receptor 3) gene. Patients with these mutations have growth defects of the long bones, skull and face. These growth defects of the face and skull are at the origin of craniomaxillofacial anomalies that may require maxillofacial bone surgeries.
FGFRs are major genes for bone formation and repair. Despite advances in medical research, the impact of these mutations on bone repair has never been studied in the craniofacial skeleton. Through their work, the results of which have just been published in the journal Bone Research, researchers at Institut Imagine have shed light on the cellular mechanisms involved in the various stages of mandibular (lower jaw) bone repair.

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Jeanne Amiel and Laurence Legeai-Mallet

Identification d’une cause génétique de défaillance de la moëlle osseuse

Anonymous — Wed, 19 Mar 2025 10:10:26 +0000

A genetic cause of an inherited bone marrow failure identified Anonymous (not verified) Wed, 03/19/2025 - 11:18

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Bone marrow is a soft tissue located within bones that is responsible for the production of blood cells, including as red blood cells, white blood cells, and platelets. Examples of genetic disorders of the bone marrow include inherited bone marrow failure syndromes. These syndromes are characterized by a total or partial impairment of the production of one or more blood cell types, which can also associate developmental delays and increased susceptibility to develop cancers. The genetic origins and symptoms of these conditions are highly varied, often leading to difficulties or even failure in diagnosis.

In a study published today in The Journal of Clinical Investigation, researchers from the laboratories Human Lymphohematopoiesis and Genome Dynamics and Human Pathologies at the Institut Imagine (Inserm, AP-HP, Université Paris Cité, CIC Biothérapie) report the identification and consequences of an OSM gene mutation in three young patients with bone marrow failure from a consanguineous family.

In 2013, patients presenting with severe bone marrow failure characterized by anemia (lack of red blood cells), neutropenia (lack of a type of white blood cell) and thrombocytopenia (lack of platelets), were referred to Patrick Revy's team for suspected telomeropathy. This group of genetic diseases is characterized by the presence of an anomaly in the size or integrity of telomeres (the ends of chromosomes, necessary to protect them from rearrangement or loss of genetic information), a frequent consequence of which is bone marrow failure. In the three patients, telomere analysis revealed no abnormalities, yet whole exome sequencing (a technique for reading the protein-producing parts of genes) identified a mutation in the OSM gene.

Following the identification of the mutation, collaboration between the laboratories and platforms of the Institut Imagine enabled the development of cellular models reproducing the effects of the mutation, thereby facilitating a more profound understanding of its impact. The Institut Imagine's Human Lymphohematopoiesis Laboratory, and more specifically Alexandrine Garrigue, Isabelle André and Chantal Lagresle-Peyrou, made a major contribution to this study. The study was also made possible by the cooperation of patients and their physicians, who facilitated the evaluation of cells harbouring the OSM mutation.

The OSM gene enables the production of the Oncostatin M (OSM) protein, particularly by immune cells (e.g. T lymphocytes, macrophages, etc.). The release of OSM into the body is crucial for its function as a signal, which is achieved by binding to membrane receptors on neighbouring cells. Examples of these receptors include OSMR (OSM receptor) and LIFR (LIF receptor). The binding of OSM to these receptors results in the regulation of various processes, including proliferation and renewal.

Initially, the research teams demonstrated that the patients' immune cells were unable to produce a functional OSM protein. Subsequently, the researchers employed the CRISPR-Cas9 molecular scissors technique to insert the OSM gene mutation identified in the patients into cell models. This confirmed that cells with the OSM mutation are unable to activate their neighboring cells. Finally, by specifically blocking the production of the normally constituted OSM protein in a zebrafish model, Swiss collaborators (Julien Bertrand, University of Geneva) observed symptoms very similar to those of the patients. This finding signifies that OSM deficiency in humans engenders highly specific clinical consequences, albeit severe, which are confined to bone marrow failure. Nevertheless, it will be crucial to monitor the emergence of any additional symptoms over time.

The elucidation of these mechanisms has the potential to unveil novel therapeutic avenues, as the current standard of care for patients with bone marrow failure due to OSM defects frequently involves blood transfusions, which only offer partial symptom relief. The present study proposes the administration of normal OSM proteins as a potential therapeutic intervention to compensate for this deficiency. Finally, this is the very first time that a genetic deficiency of OSM has been described in humans, while many cases of excessive OSM synthesis have already been observed in inflammatory diseases such as multiple sclerosis, Crohn's disease or rheumatoid arthritis. This is why antibodies or inhibitors directed against OSM and OSMR are currently in clinical trials. However, the deleterious consequences of an OSM defect on hematopoiesis described by the Institut Imagine laboratories suggest that the inappropriate use of drugs targeting OSM could have considerable adverse effects.

The article, published in the journal in The Journal of Clinical Investigation, is accompanied by a detailed commentary by two researchers from the Catholic University of Leuven (KU Leuven, Belgium).

References :

Garrigue A, Kermasson L, Susini S, Fert I, Mahony CB, Sadej H, Luce S et al. (2025) Human oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome. J Clin Invest. 135(6):e180981

DOI: 10.1172/JCI180981

Corresponding authors: Patrick Revy & Chantal Lagresle-Peyrou

Delafontaine S & Meyts I (2025) Oncostatin M silence and neopeptide: the value of exploring patients with rare inherited bone marrow failure. J Clin Invest. 135(6):e190955

DOI: 10.1172/JCI190955

Accroche

Inherited bone marrow failure syndromes (IBMFS) are rare diseases that affect the production of one or more types of blood cells by the bone marrow. Patients suffering from IBMFS are predisposed to an increased risk of infection, bleeding and serious complications. The diagnosis of IBMFS is often complex, due to the diversity of genetic causes. In a study published in The Journal of Clinical Investigation (JCI), researchers from the Institut Imagine report for the first time ever the consequences of Oncostatin M (OSM) deficiency in humans. This achievement was made possible by the identification of a mutation in the OSM gene in three young patients suffering from severe bone marrow failure, resulting in the production of an abnormal OSM protein. To determine the effect of this mutation, the researchers used CRISPR-Cas9 molecular scissors to reproduce the mutation in cell models. This approach enabled the demonstration that the mutated form of the OSM protein had lost its activating capacity. Furthermore, a concomitant report by a Saudi Arabian team of three new patients with a different mutation of the OSM gene and similar symptoms confirms the key role of this protein in blood cell production. This pioneering discovery present novel therapeutic prospects for these patients, including the administration of Oncostatin M, which would serve as a substitute for blood transfusions, a common treatment in severe anemia.

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Patrick Revy and Erika Brunet

Les découvertes génétiques pionnières de Jean-Laurent Casanova lui valent le prix Novo Nordisk 2025

Anonymous — Mon, 24 Feb 2025 09:39:34 +0000

Jean-Laurent Casanova’s pioneering genetic discoveries earn him the 2025 Novo Nordisk Prize Anonymous (not verified) Mon, 02/24/2025 - 11:14

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Jean-Laurent Casanova’s research, spanning more than three decades, has shown that rare or not-so-rare genetic mutations can make some
individuals especially vulnerable to infections that others shrug off. “Why would a child be hospitalised for viral pneumonia, tuberculosis or any other severe infection when most children infected with the very same microbe do well? That is what I call the infection enigma,” he explains.
His pioneering work has uncovered more than 70 genes that, when mutated, impair the body’s ability to fight off specific infections. This
research has not only deepened understanding of human immunity but also led to new possibilities for patient care – helping clinicians better
predict, diagnose and treat infectious diseases based on individual genetic profiles.

Recognising a landmark scientific contribution

Mads Krogsgaard Thomsen, CEO of the Novo Nordisk Foundation, emphasises the significance of Jean-Laurent Casanova’s contributions: “His work exemplifies the power of integrating clinical observation with genetic research. By uncovering the genetic basis of susceptibility to infections, Professor Casanova has opened new avenues for personalised medicine,
offering hope for more effective treatments and preventive strategies.” Professor Jørgen Frøkiær, Chair of the Novo Nordisk Prize Committee,
adds: “Jean-Laurent Casanova’s research has transformed understanding of infectious diseases by revealing the critical role of genetic factors. His
discoveries have provided new insight into why some individuals are more vulnerable to infections, paving the way for novel approaches in
immunology and public health.”

For Jean-Laurent Casanova, the recognition is a surprise but also validates a career dedicated to reshaping how we understand infections. “When I got
the call, I had no idea I had even been nominated,” he says. “But this is by far the most important award I have received in my career, and I am
incredibly honoured.”

The 2025 Novo Nordisk Prize will be awarded at a ceremony in Bagsværd, Denmark, on April 25, to Professor Jean-Laurent Casanova from Necker
Medical School in Paris, France and the Rockefeller University in New York, USA. A Prize Lecture by Jean-Laurent Casanova will take place at the
Panum Institute, University of Copenhagen, Denmark in the Niels K. Jerne Auditorium, Building 13 on April 24, the day before the official award
ceremony.

About Jean-Laurent Casanova
• 1987 MD, University of Paris Descartes, France
• 1992 PhD in Immunology, University of Paris Pierre and Marie Curie, France
• 1999 Professor of Paediatrics, Necker Medical School, Paris, France
• 1999 Co-founder, Laboratory of Human Genetics of Infectious Diseases, Institut Imagine, Paris, France, Inserm, AP-HP, Université Paris Cité
• 2008 Professor, the Rockefeller University, New York
• 2014 Investigator, Howard Hughes Medical Institute, Chevy Chase, MD, USA
• 2015 Foreign Member, United States National Academy of Sciences
• 2015 Foreign Member, United States National Academy of Medicine

About the Novo Nordisk Prize
The Novo Nordisk Prize recognises active scientists who have provided outstanding international contributions to advance medical science to
benefit people’s lives. The prize is awarded annually by the Novo Nordisk Foundation and is intended to further support biomedical research in
Europe.

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For decades, scientists believed that infections were determined solely by viruses and bacteria. But Professor Jean-Laurent Casanova’s groundbreaking research has revealed a more complex reality: genes play a fundamental role in determining who gets seriously ill and who stays healthy. Because of his pioneering discoveries, he is being honoured and awarded with the 2025 Novo Nordisk Prize.

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Jean-Laurent Casanova