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1. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy

Author

Caroline Le Guiner, Laurent Servais, Marie Montus, Thibaut Larcher, Bodvaël Fraysse, Sophie Moullec, Marine Allais, Virginie François, Maeva Dutilleul, Alberto Malerba, Taeyoung Koo, Jean-Laurent Thibaut, Béatrice Matot, Marie Devaux, Johanne Le Duff, Jack-Yves Deschamps, Inès Barthelemy, Stéphane Blot, Isabelle Testault, Karim Wahbi, Stéphane Ederhy, Samia Martin, Philippe Veron, Christophe Georger, Takis Athanasopoulos, Carole Masurier, Federico Mingozzi, Pierre Carlier, Bernard Gjata, Jean-Yves Hogrel, Oumeya Adjali, Fulvio Mavilio, Thomas Voit, Philippe Moullier, and George Dickson

Subjects
Science
Abstract

Duchenne muscular dystrophy is a progressive degenerative disease of muscles caused by mutations in the dystrophin gene. Here the authors use AAV vectors to deliver microdystrophin to dogs with muscular dystrophy, and show restoration of dystrophin expression and reduction of symptoms up to 26 months of age.

Published
2017
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3. Standardized and axially vascularized calcium phosphate-based implants for segmental mandibular defects: A promising proof of concept

Author

Arnaud Paré, Baptiste Charbonnier, Joëlle Veziers, Caroline Vignes, Maeva Dutilleul, Gonzague De Pinieux, Boris Laure, Adeline Bossard, Annaëlle Saucet-Zerbib, Gwenola Touzot-Jourde, Pierre Weiss, Pierre Corre, Olivier Gauthier, and David Marchat

Subjects
Biomaterials, Biomedical Engineering, General Medicine, Molecular Biology, Biochemistry, Biotechnology
Abstract

The reconstruction of massive segmental mandibular bone defects (SMDs) remains challenging even today; the current gold standard in human clinics being vascularized bone transplantation (VBT). As alternative to this onerous approach, bone tissue engineering strategies have been widely investigated. However, they displayed limited clinical success, particularly in failing to address the essential problem of quick vascularization of the implant. Although routinely used in clinics, the insertion of intrinsic vascularization in bioengineered constructs for the rapid formation of a feeding angiosome remains uncommon. In a clinically relevant model (sheep), a custom calcium phosphate-based bioceramic soaked with autologous bone marrow and perfused by an arteriovenous loop was tested to regenerate a massive SMD and was compared to VBT (clinical standard). Animals did not support well the VBT treatment, and the study was aborted 2 weeks after surgery due to ethical and animal welfare considerations. SMD regeneration was successful with the custom vascularized bone construct. Implants were well osseointegrated and vascularized after only 3 months of implantation and totally entrapped in lamellar bone after 12 months; a healthy yellow bone marrow filled the remaining space. STATEMENT OF SIGNIFICANCE: Regenerative medicine struggles with the generation of large functional bone volume. Among them segmental mandibular defects are particularly challenging to restore. The standard of care, based on bone free flaps, still displays ethical and technical drawbacks (e.g., donor site morbidity). Modern engineering technologies (e.g., 3D printing, digital chain) were combined to relevant surgical techniques to provide a pre-clinical proof of concept, investigating for the benefits of such a strategy in bone-related regenerative field. Results proved that a synthetic-biologics-free approach is able to regenerate a critical size segmental mandibular defect of 15 cm

Published
2022

4. Pain Management After Bone Reconstruction Surgery Using an Analgesic Bone Cement: A Functional Noninvasive In Vivo Study Using Gait Analysis

Author

Pascal Janvier, Jean-Michel Bouler, Maeva Dutilleul, Elise Verron, Manon Dupleichs, Olivier Gauthier, M. Masson, Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université de Nantes - UFR Odontologie, Université de Nantes (UN), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), and Jehan, Frederic

Subjects
medicine.medical_specialty, medicine.medical_treatment, Analgesic, 02 engineering and technology, Bone grafting, Iliac crest, Bone and Bones, 03 medical and health sciences, Bone pain, 0302 clinical medicine, medicine, Animals, Pain Management, Orthopedic Procedures, CatWalk gait analysis, Anesthetics, Local, Pain Measurement, Bupivacaine, Pain, Postoperative, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Ropivacaine, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Bone Cements, calcium phosphate cement, Plastic Surgery Procedures, drug-device combination, 021001 nanoscience & nanotechnology, Bone cement, local anesthetic drug, Rats, Surgery, Anesthesiology and Pain Medicine, medicine.anatomical_structure, Neurology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Gait analysis, Neurology (clinical), medicine.symptom, Gait Analysis, 0210 nano-technology, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; Abstract: Postoperative pain after bone reconstruction is a serious complication that could jeopardize the global success of a surgery. This pain must be controlled and minimized during the first 3 to 4 postoperative days to prevent it from becoming chronic. In this study, a critical-size bone defect was created at the femoral distal end of rats and filled by an injectable calcium phosphate cement (CPC) loaded or not with local anesthetics (bupivacaine or ropivacaine). A functional evaluation of the gait was performed using the CatWalk system to compare the postoperative pain relief enhanced by the different CPCs after such a bone filling surgery. The results demonstrated significant pain relief during the short-term postoperative period, as shown by the print area and intensity parameters of the operated paw. At 24 hours, the print area decreased by 65%, 42%, and 24%, and the intensity decreased by 25%, 9%, and 1% for unloaded, ropivacaine-loaded, and bupivacaine-loaded CPCs, respectively, compared with the preoperative values. Bupivacaine-loaded CPC provided an earlier return to full functional recovery than ropivacaine-loaded CPC. Moreover, the CPCs retained their biologic and mechanical properties. For all these reasons, anesthetic-loaded CPCs could be part of the global pain management protocol after bone reconstruction surgery such as iliac crest bone grafting procedures.Perspective: Bupivacaine-loaded CPC provided an earlier return to full gait function than ropiva-caine-loaded CPC, with preserved bone filling properties. Such analgesic CPCs deserve further in vivo investigation and may be part of the global pain management protocol after bone reconstruction or bone augmentation surgery such as iliac crest bone grafting.

Published
2018

5. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy

Author

Virginie François, Oumeya Adjali, Jean-Yves Hogrel, George Dickson, Thibaut Larcher, Maeva Dutilleul, Taeyoung Koo, Marie Montus, Stéphane Ederhy, Stéphane Blot, M. Allais, Carole Masurier, Alberto Malerba, Marie Devaux, B. Matot, Karim Wahbi, Sophie Moullec, Bernard Gjata, Bodvael Fraysse, Laurent Servais, Fulvio Mavilio, Inès Barthélémy, Pierre G. Carlier, Takis Athanasopoulos, Isabelle Testault, Samia Martin, Jack-Yves Deschamps, Philippe Moullier, Federico Mingozzi, Philippe Veron, Christophe Georger, Johanne Le Duff, Caroline Le Guiner, Thomas Voit, Jean-Laurent Thibaut, U1089, Institut National de la Santé et de la Recherche Médicale (INSERM), Service of Clinical Trials and Databases, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Généthon, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Boisbonne, Atlantic Gene Therapies, Ecole Nationale Vétérinaire Agroalimentaire et de l'Alimentation Nantes Atlantique (ONIRIS), Thérapie génique translationnelle pour les maladies neuromusculaires et de la rétine, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Royal Holloway, University of London, Laboratoire de Résonance Magnétique Nucléaire (LRMN), Modélisation thérapeutique en neurologie: myologie et biothérapies des myopathies canines, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Chercheur indépendant, Centre Hospitalier Vétérinaire Atlantia, Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire des Sciences de l'Information et des Systèmes (LSIS), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Arts et Métiers Paristech ENSAM Aix-en-Provence-Centre National de la Recherche Scientifique (CNRS), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, University of Wolverhampton, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMR1089, Laboratoire de Thérapie Génique, Université de Nantes (UN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Service de Cardiologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Arts et Métiers Paristech ENSAM Aix-en-Provence-Université de Toulon (UTLN)-Aix Marseille Université (AMU), École pratique des hautes études (EPHE), Laboratoire RMN, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMR 1089, Atlantic Gene Therapies, Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Association française contre les myopathies (AFM-Téléthon), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1089, Atlantic Gene Therapies & Genethon, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Recherche et développement [Généthon, Evry] (R & D Généthon), Généthon [Evry], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)

Subjects
0301 basic medicine, Male, myopathie de duchenne, Duchenne muscular dystrophy, Genetic enhancement, medicine.medical_treatment, General Physics and Astronomy, Bioinformatics, Dystrophin, Muscular Dystrophy, Vector (molecular biology), Transgenes, Muscular dystrophy, Multidisciplinary, biology, Gene Transfer Techniques, Immunosuppression, Skeletal, Dependovirus, 3. Good health, thérapie génique, Administration, Muscle, Administration, Intravenous, Intravenous, ITGA7, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Neuromuscular disease, Science, Genetic Vectors, Animals, Disease Models, Animal, Dogs, Genetic Therapy, Muscle, Skeletal, Muscular Dystrophy, Animal, Muscular Dystrophy, Duchenne, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Animal, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Duchenne, medicine.disease, 030104 developmental biology, Disease Models, biology.protein, business
Abstract

Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV–microdystrophin gene therapy in DMD patients., Duchenne muscular dystrophy is a progressive degenerative disease of muscles caused by mutations in the dystrophin gene. Here the authors use AAV vectors to deliver microdystrophin to dogs with muscular dystrophy, and show restoration of dystrophin expression and reduction of symptoms up to 26 months of age.

Published
2017

6. A straightforward approach to enhance the textural, mechanical and biological properties of injectable calcium phosphate apatitic cements (CPCs): CPC/blood composites, a comprehensive study

Author

Myriam Le Ferrec, Jean-Michel Bouler, Franck Fayon, Charlotte Mellier, Alain Walcarius, Christelle Despas, Pascal Janvier, Olivier Gauthier, Florian Boukhechba, Bruno Bujoli, Maeva Dutilleul, François-Xavier Lefèvre, Valérie Montouillout, Graftys SARL, Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Conditions Extrêmes et Matériaux : Haute Température et Irradiation (CEMHTI), Université d'Orléans (UO)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie Physique et Microbiologie pour l'Environnement (LCPME), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université d'Orléans (UO), Jehan, Frederic, Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Regenerative Medicine and Skeleton (RMeS), and École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE)

Subjects
Ceramics, Materials science, Scanning electron microscope, 0206 medical engineering, Composite number, Biomedical Engineering, chemistry.chemical_element, Blood clot, 02 engineering and technology, Calcium, Biochemistry, Biomaterials, Osteogenesis, Apatites, Materials Testing, In vivo, Animals, Composite material, Bone regeneration, Porosity, Molecular Biology, Cement, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Precipitation (chemistry), Organic and inorganic networks, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Bone Cements, General Medicine, 021001 nanoscience & nanotechnology, Microstructure, 020601 biomedical engineering, chemistry, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rabbits, Calcium phosphate composites, 0210 nano-technology, Biotechnology
Abstract

International audience; Two commercial formulations of apatitic calcium phosphate cements (CPCs), Graftys Ò Quickset (QS) and Graftys Ò HBS (HBS), similar in composition but with different initial setting time (7 and 15 min, respectively), were combined to ovine whole blood. Surprisingly, although a very cohesive paste was obtained after a few minutes, the setting time of the HBS/blood composite dramatically delayed when compared to its QS analogue and the two blood-free references. Using solid state NMR, scanning electron microscopy and high frequency impedance measurements, it was shown that, in the particular case of the HBS/blood composite, formation of a reticulated and porous organic network occurred in the intergranular space, prior to the precipitation of apatite crystals driven by the cement setting process. The resulting microstructure conferred unique biological properties to this material upon implantation in bone defects, since its degradation rate after 4 and 12 weeks was more than twice that for the three other CPCs, with a significant replacement by newly formed bone. Statement of Significance A major challenge in the design of bone graft substitutes is the development of injectable, cohesive, resorbable and self-setting calcium phosphate cement (CPC) that enables rapid cell invasion with initial mechanical properties as close as bone ones. Thus, we describe specific conditions in CPC-blood composites where the formation of a 3D clot-like network can interact with the precipitated apatite crystals formed during the cement setting process. The resulting microstructure appears more ductile at short-term and more sensitive to biological degradation which finally promotes new bone formation. This important and original paper reports the design and in-depth chemical and physical characterization of this groundbreaking technology.

Published
2017

7. Understanding the mechanisms of notochord maturation and transformation during intervertebral disc morphogenesis in the mouse

Author

Antoine Henry, Pauline Colombier, Maeva Dutilleul, Florent Autrusseau, Jérôme Guicheux, Anne Camus, Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), UMR791, Laboratoire d’Ingénierie Ostéo-Articulaire et Dentaire, OTONN PHU4 CHU de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM), Développement et Pathologie du Tissu Musculaire (DPTM), and Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes

Subjects
[SDV.BC]Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2017

8. Characterization of Dystrophin Deficient Rats: A New Model for Duchenne Muscular Dystrophy

Author

Laurent Tesson, Helicia Goubin, Jean-Baptiste Renaud, Thibaut Larcher, Caroline Le Guiner, Yan Cherel, Carine Giovannangeli, Corinne Huchet, Maeva Dutilleul, Ignacio Anegon, Gilles Toumaniantz, Anne De Cian, Lydie Guigand, Jean-Paul Concordet, Séverine Remy, Charlotte Boix, A. Lafoux, Virginie François, Virginie Thepenier, Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Atlantic Gene Therapies, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de Transplantation Urologie-Néphrologie (ITUN), Institut de Transplantation Urologie-Néphrologie ( ITUN), Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Généthon, Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Région Pays de la Loire (Biogenouest), IBiSA program, Fondation Progreffe, TEFOR (Infrastructures d'Avenir du Gouvernement Français), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes (UN), APEX - Plate-forme d'expertise en anatomie pathologique pour la Recherche [Nantes] (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-INRA - Oniris (INRA UMR0703), Institut National de la Recherche Agronomique (INRA)-Institut National de la Recherche Agronomique (INRA), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Thérapie génique translationnelle pour les maladies neuromusculaires et de la rétine, Recherche et développement [Généthon, Evry] (R & D Généthon), Généthon [Evry], Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Région Pays de la Loire through Biogenouest, IBiSA program, Fondation Progreffe and TEFOR (Infrastructures d’Avenir of the French goverment), and the integrative genomic facility of Nantes for sequencing experiments., Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Unité de recherche de l'institut du thorax (ITX-lab), Le Bihan, Sylvie, and Lafoux, Aude

Subjects
Male, Pathology, Necrosis, myopathie de duchenne, Physiology, Duchenne muscular dystrophy, Gene Expression, Adipose tissue, Dystrophin, 0302 clinical medicine, Medicine and Health Sciences, Medicine, rat, Muscular dystrophy, Creatine Kinase, 0303 health sciences, Muscle Weakness, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Ventricular Remodeling, biology, Dilated cardiomyopathy, Exons, Diaphragm (structural system), Neurology, Gene Targeting, Female, medicine.symptom, Research Article, Biotechnology, musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Science, Médecine humaine et pathologie, modèle d'analyse, 03 medical and health sciences, Genetics, Congenital Disorders, Animals, RNA, Messenger, Muscle, Skeletal, Molecular Biology, 030304 developmental biology, Base Sequence, business.industry, Myocardium, Biology and Life Sciences, Muscle weakness, Cell Biology, Muscular Dystrophy, Animal, medicine.disease, Fibrosis, Rats, Muscular Dystrophy, Duchenne, Disease Models, Animal, Mutation, biology.protein, Human health and pathology, business, mutant déficient, Gene Deletion, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmd[mdx]) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmd[mdx] rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmd[mdx] rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmd[mdx] rats represent a new faithful small animal model of DMD.

Published
2014

9. Locoregional intravenous delivery of AAV vector in macaque results in persistent transgene expression despite a dedicated humoral and cellular immune response

Author

Gwladys Gernoux, Marie Devaux, Laurence Dubreil, Nicolas Jaulin, Mickaël Guilbaud, Jack-Yves Deschamps, Thibaut Larcher, Lydie Guigand, Maeva Dutilleul, Caroline Le Guiner, Yan Cherel, Philippe Moullier, Oumeya Adjali, Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, University of Florida [Gainesville], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes (UN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), University of Florida [Gainesville] (UF), American Society of Cell and Gene Therapy (ASGCT). USA., Department of Molecular Genetics and Microbiology [Gainesville] (UF|MGM), Department of Medicine [Gainesville] (UF|Medicine), and University of Florida [Gainesville] (UF)-University of Florida [Gainesville] (UF)

Subjects
Innate immunity, Adaptive immunology, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Immunité innée, [SDV]Life Sciences [q-bio], fungi, aav, Biotechnologies, réponse immunitaire humorale, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Immunité adaptative, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, macaca mulatta, vecteur d'expression génique, réponse immunitaire innée, ComputingMilieux_MISCELLANEOUS
Abstract

After LR delivery of an AAV8 vector expressing GFP in non-human primates, we showed detection of transgene expression until at least 8 months post-injection in contrast to IM where GFP was lost at 3 months post-injection. Interestingly, GFP persistence after LR was observed despite the detection of anti-GFP IgG antibodies, even at higher titers than IM route, and the presence of T cells responding to GFP peptides in the spleen. Surprisingly, GFP-restimulated T cells secreted IFNγ but not IL2 after LR as compared to IM route where both cytokines were detected.

Published
2013

10. G.P.92

Author

Yan Cherel, Philippe Veron, F. Barnay-Toutain, Virginie Latournerie, Christian Leborgne, Jean-Laurent Thibaud, Marie Montus, Claire Wary, Nicolas Jaulin, C. Le Guiner, Claire Domenger, Christel Rivière, Oumeya Adjali, H. Goubin, T. Voit, Carole Masurier, Lydie Guigand, N. Delaunay, Philippe Moullier, Sylvie Boutin, Diana Desgue, B. Matot, Gisèle Bonne, Virginie François, J.Y. Hogrel, Maeva Dutilleul, L. Servais, Pierre G. Carlier, Marie Devaux, M. Allais, Sophie Moullec, J. Le Duff, Mickaël Guilbaud, Jack-Yves Deschamps, and T. Larche

Subjects
Pathology, medicine.medical_specialty, Muscle biopsy, medicine.diagnostic_test, biology, Transgene, Reversion, Molecular biology, Exon skipping, Viral vector, law.invention, Neurology, law, Pediatrics, Perinatology and Child Health, medicine, Recombinant DNA, biology.protein, Neurology (clinical), Dystrophin, Perfusion, Genetics (clinical)
Abstract

We have previously demonstrated that a recombinant adeno-associated virus vector, serotype 8 (rAAV8) carrying a modified U7snRNA sequence promoting exon skipping injected in GRMD by locoregional transvenous perfusion of the forelimb, restores up to 80% dystrophin expression and improves histological, Nuclear Magnetic Resonance (NMR) pathological indices and strength in a dose-dependent manner at 3 months post injection (PInj). A recent paper suggested that dystrophin-positive fibers and rAAV genome drastically decrease with time, especially between 3 and 6 months PInj. This may compromise the clinical development of an AAV-mediated gene transfer approach. To assess this point, we realized a 6 to 7 months follow-up in a group of 3 GRMD aged 3–4 months when injected in both forelimbs with 2.5E13 vg/kg of a rAAV8 U7snRNA vector promoting exon skipping. Dogs were injected, followed up and evaluated (NMR, strength assessment, Dystrophin expression, vector biodistribution) in the same way as the previously reported large cohort of dogs that were followed for 3 months. Muscle biopsies were performed at 3 months and complete autopsy at 6 to 7 months PInj. Compared to previously reported dogs injected with the same dose, evaluation of dystrophin expression, histological aspect, AAV genome, NMR parameters and strength showed not differences indicating that the treatment effect was fully maintained over 6 months. No loss in AAV genome quantification and dystrophin expression was observed between the 3 months muscle biopsy specimens and 6 months muscle autopsy in the 3 dogs. A decrement in transgene copy numbers at 6 months PInj was observed in non muscular tissues. These data show, for the first time, that AAV-mediated exon skipping fully maintains dystrophin expression and functional recovery over a six months period. We suggest that long-term rAAV genome stability is obtained in dystrophic muscles when a substantial reversion of the muscular pathological pattern is reached.

Published
2014

11. Macaque immune responses following AAV-based gene transfer to the skeletal muscle: addressing the method of vector delivery

Author

Gwladys Gernoux, Marie Devaux, Laurence Dubreil, Nicolas Jaulin, Mickaël Guilbaud, Jack-Yves Deschamps, Thibaut Larcher, Lydie Guigand, Maeva Dutilleul, Yan Cherel, Philippe Moullier, Oumeya Adjali, Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Department of Molecular Genetics and Microbiology [Gainesville] (UF|MGM), Department of Medicine [Gainesville] (UF|Medicine), and University of Florida [Gainesville] (UF)-University of Florida [Gainesville] (UF)

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

12. Characterization of dystrophin deficient rats: a new model for Duchenne muscular dystrophy.

Author

Thibaut Larcher, Aude Lafoux, Laurent Tesson, Séverine Remy, Virginie Thepenier, Virginie François, Caroline Le Guiner, Helicia Goubin, Maéva Dutilleul, Lydie Guigand, Gilles Toumaniantz, Anne De Cian, Charlotte Boix, Jean-Baptiste Renaud, Yan Cherel, Carine Giovannangeli, Jean-Paul Concordet, Ignacio Anegon, and Corinne Huchet

Subjects
Medicine, Science
Abstract

A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD.

Published
2014
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