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Institut Mondor de Recherche Biomédicale

Institut Mondor de Recherche Biomédicale

57 Projects, page 1 of 12
  • Funder: ANR Project Code: ANR-23-CE17-0049
    Funder Contribution: 619,400 EUR

    Inclusion body myositis (IBM) differs from other autoimmune myositis by its poor response to immunosuppressant therapies, and degenerative muscular features leading to marked disability. IBM is characterized by a strong IFN-gamma (IFN?) signature in muscle tissue, which is related to the CD8+ T-cells infiltrating muscles and producing large amounts of IFN?. The pathophysiology of IBM has been mainly regarded from the view of immune response, so that the mechanisms leading to muscle degenerative features remains largely unknown. We previously showed that (i) in IBM, muscle cells themselves display evidences for IFN? signaling; (ii) in vitro, IFN? impairs the proliferation and differentiation of myogenic cells and will induce their senescence; and (iii) in vivo, the combination of a muscular injury with IFN? administration is sufficient to reproduce some degenerative muscular features of IBM. In addition, we also showed that in IBM, IFN? signature strongly correlates with primary cilium signature. From these results, we hypothesized that IFN? could be the key factor of muscular degeneration in IBM and primary cilium disrupting and/or dysfunction could, at least in part, mediate the pathogenic effects of IFN? in IBM. Our project aims (i) to dissect at the cell and molecular levels the effects of IFN? in IBM patients by using single nucleus RNAseq and spatial transcriptomics; (ii) to analyze in vitro the effects of IFN? on primary cilium on human myogenic cells; (iii) to deepen the in vivo effects of IFN? on skeletal muscle biology with a special attention to primary cilium structure and function; and (iv) to validate in patients the experimental results dealing with the effects of IFN? on primary cilium. Evidencing that IBM is an acquired IFN?-driven ciliopathy represents a conceptual breakthrough in myology. Primary cilium has never been investigated in the context of muscular diseases. We believe that present project will pioneer the field of muscular ciliopathy.

  • Funder: ANR Project Code: ANR-21-MRS1-0005
    Funder Contribution: 29,680 EUR

    Skeletal muscle is a critical target organ to treat or prevent a large variety of disorders, collectively belonging to Neuromuscular Disorders. With skeletal muscle being the largest tissue of our body (representing 30-40% of total body mass), neuromuscular disorders greatly impair quality of life and pose a heavy financial burden to the European health care system. In addition, skeletal muscle atrophy is a hallmark of aging and cancer-related afflictions, leading to muscle weakness and increased risk of falls and hospitalization. Despite the high burden of these greatly prevalent pathologies, there is currently no definite therapy and clinical trial attempts have not provided positive results for the vast majority of them. We will develop advanced therapeutic interventions that will enhance muscle regenerative capacity, with the ultimate goal of prolonging health span as well as lifespan. We will investigate two mechanistically distinct genetic causes of muscle degeneration, Duchenne Muscular Dystrophy (DMD) and FacioscapuloHumeral Muscular Dystrophy (FSHD), as two major genetic causes leading to muscle wasting and degeneration without therapeutic options. The MuscleDARE consortium will unite academic and industrial partners to establish a personalized therapeutic platform and a proof-of-concept pipeline for genome editing gene therapy to treat these emblematic neuromuscular disorders. Our research program is organized along 3 interconnected axes: 1. Preclinical efficiency, specificity and safety evaluation: Proof-of-principle in large animal models for CRISPR/Cas9-based correction of muscle stem cells (MuSCs), development of viral and non-viral delivery systems, innovative multiparametric evaluation and complementary pharmaceutical improvement. --> Focus on MuSC targeting promises long-lasting persistence of strengthened myofibers and long-term therapeutic benefits, in contrast to common treatments that provide no lasting effects or cure. --> A major axis of our program will be immunogenicity considerations and safety evaluation to enhance the translational value of the developed advanced therapies. 2. Personalized therapeutics: Establish a therapeutic workflow that will translate in patient iPSC-based and organoid-based genome editing platform. Given the variety of mutations that underlie neuromuscular disorders, including DMD and FSHD, this personalized platform will help us expand the developed therapeutic benefit to virtually any patient. 3. Personalized medicine: Recruit patient cohorts, design state-of-the-art patient evaluation and care, and prepare for a clinical trial in strict compliance with regulatory requirements. In summary, the basic-to-clinical pipeline that will be established will provide personalized genome editing advanced therapeutics that can be used in a vast number of monogenic diseases afflicting a major part of the European population.

  • Funder: ANR Project Code: ANR-20-COVI-0045
    Funder Contribution: 99,360 EUR

    SARS-CoV-2 has emerged at the end of December 2019 in China, causing a new worldwide pandemic of pneumonia. As of today, more than 260,000 people have been infected and more than 11,000 have died. There is no known antiviral treatment for coronavirus infections. Empirical attempts are being made, with disappointing results thus far. The host cell proteins cyclophilins play a key role in the lifecycle of many coronaviruses. We raise the hypothesis that cyclophilin inhibitors will provide highly efficacious antiviral solutions against SARS-CoV-2 infection, with a high barrier to viral resistance. Alisporivir (DEBIO-025) is a non-immunosuppressive macrocyclic cyclosporine A analog endowed with powerful cyclophilin inhibitory properties, likely to be active against SARS-CoV-2, that has already been administered to over 2000 patients in Phase 2 or 3 trials for another antiviral indication and has proven to be safe and well tolerated as a monotherapy. Preliminary results indicate that alisporivir inhibits the lifecycle of various coronaviruses, including HCoV-229E, HCoV-OC43 and MERS-CoV. The objectives of this project are: (i) To assess and fully characterize the antiviral effect of alisporivir on SARS-CoV-2 to provide in vitro evidence paving the way to a rapid clinical repositioning of alisporivir in this indication. (ii) To understand the molecular mechanisms underlying the antiviral effect of alisporivir against SARS-CoV-2. (iii) To bring the proof-of-concept that a new family of small-molecule, non-peptidic cyclophilin inhibitors active against other respiratory viral infections are also active against SARS-CoV-2 and could be developed in the future to prevent a new pandemic. Our results will provide the rationale for a rapid repositioning of alisporivir in the treatment of SARS-CoV-2 infection. The design of a planned clinical trial will be based on the results of the project, in particular the proof-of-concept of antiviral effectiveness, understanding of the dynamics of viral inhibition, and understanding of the antiviral mechanisms of action (especially, the life cycle step inhibited), that will guide the best indication(s) and treatment schedule.

  • Funder: ANR Project Code: ANR-23-CE17-0041
    Funder Contribution: 380,225 EUR

    Congenital myopathies (CM) are severe monogenic muscle diseases affecting humans from birth or early infancy and having a strong impact on patient survival and quality of life leading to muscle weakness provoking in some cases gait loss. Nemaline Myopathy (NEM) and Cap myopathy, are two of the most common CM with an estimated frequency of 1 in 50,000 live births. They are characterized by the presence of protein inclusions with a rod shape (rods) and cap in the muscle biopsy. In 2017 we and others have reported a CM caused by biallelic mutations in the myopalladin gene MYPN, leading to loss of function of MYPN, with rods and caps in the myofibers. MYPN-CM are rare, they have an important impact on patients’ quality of life resulting from early onset muscle weakness possibly leading to gait loss, and have no cure. The monogenic nature of MYPN-CM, and the size of MYPN gene made MYPN-CM suitable for AAV mediated therapeutic approaches. Nevertheless, their rarity precludes appeal for pharmaceutical companies. Recent studies in a murine MYPN knock out model (MKO) demonstrated that MYPN promotes skeletal muscle growth through activation of the SRF pathway. Our MKO muscles myopathologic analysis showed myofibers atrophy, increased nuclear internalizations, and ring-shape fibers, reminiscent of caps, never reported before. An innovative technique developed in our lab that consists in creating a model of 3D mature myofibers derived from MKO muscle satellite cells (MuSCs) cultured in vitro on innovative hydrodynamic gels (3DMM) showed that MKO MuSCs exhibited a-actinin striation, dissolution at Z-line levels, a-actinin accumulation in some myofibers, and prominent centrally placed nuclei. With the goal of developing a therapeutic strategy for MYPN-CM, we will employ a translational approach using complementary preclinical models, 3DMM and MKO with these specific aims: 1. Definition of molecular (sNuclei RNA seq), myopathologic, and clinical readouts; 2. AAV-based gene therapy strategy development and in vitro validation on 3DMM; 3. Evaluation of the therapeutic benefit in vivo in MKO. The clinico-myopathologic expertise of the coordinator, the presence of a clear myopathologic phenotype (ring fibers etc.) in MKO and 3DMM, the utilization or cutting edge RNASeq techniques perfectly mastered in our lab, together with the know-how on AAV gene rescuing strategies for myopathies (Généthon, collaboration) will allow to accelerate the gene therapy development and to comprehend the molecular mechanisms underlying MYPN-CM. The full academic setting of this project will serve as template to develop the therapy of other rare CMs.

  • Funder: ANR Project Code: ANR-22-ASTR-0034
    Funder Contribution: 299,700 EUR

    In most cases of muscle injury, the remarkable regenerative capacity of the adult skeletal muscle allows the repair of damaged muscle fibers and full functional recovery. However, in case of a massive ablation of muscle mass, called Volumetric Muscle Loss (VML), the biophysical and cellular components orchestrating muscle regeneration are lost, leading to replacement of muscle tissue by fibrous tissue and chronic functional deficits. These injuries affect both civilian and military populations, since they are most often the result of accidental or iatrogenic traumatic events, or injuries caused by firearms or explosive devices in the military. Despite the incidence and severity of VML injuries, treatment options remain very limited and most of the patients suffer from chronic disability, which generates particularly heavy socio-economic impacts over the long term. Given the complexity of these lesions and the lack of therapeutic options, the repair of VML is a major challenge for regenerative medicine. The bioengineering of 3D implantable muscle constructs able to restore normal muscle function would represent a significant advance in the repair of VML lesions. The development of such 3D constructs relies essentially on the association of a biomaterial, capable of reproducing the topography of the muscle, with myogenic cells. Despite the major advances made in this field in recent years, none of the tissue engineering approaches proposed so far allow to envisage a transfer to the clinic. We have developed biocompatible hydrogels whose topographic and biomechanical properties seem to be adapted to this type of application. In addition, we have acquired within the laboratory a unique expertise in the purification and in vitro expansion of human muscle stem cells for clinical purposes as well as in the myogenic differentiation of human iPSCs. In this context, with this HydraCell project, we propose to take advantage of these different expertises to develop tissue engineering approaches based on the implantation of our hydrogels associated with muscle stem cells or iPSCs for VML repair.


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