Cell therapy of Duchenne muscular dystrophy: preclinical trial in GRMD dogs

Duchenne muscular dystrophy (DMD), a genetic progressive X-linked muscular dystrophy, is the most common genetic disease in humans. Cell therapy based on the use of somatic stem cells is a very promising approach. In a dog myopathy model, we isolated a muscle stem cell (MuStem) with the essential requirements for therapeutic use: high amplification capacity, ability to fuse with muscle fibers, renewal of the satellite cell population, dispersion in the whole body after vascular administration, persistence of long-term effect, and dramatic clinical improvement of treated animals. These preclinical results pave the way for a therapeutic trial in children with Duchenne muscular dystrophy.La dystrophie musculaire de Duchenne (DMD) est une maladie génétique progressive du muscle liée au chromosome X. Elle est la maladie génétique la plus fréquente chez l'homme. La thérapie cellulaire basée sur l'utilisation de cellules souches somatiques est une voie thérapeutique riche d'intérêt. Nous avons isolé, chez un modèle de chien myopathe, une cellule souche musculaire (MuStem) qui présente les qualités indispensables à une utilisation thérapeutique: forte capacité d'amplification, capacité à fusionner avec les fibres musculaires, renouvellement du contingent de cellules satellites, dispersion dans l'organisme après administration vasculaire, persistance de l'effet à long terme, spectaculaire amélioration clinique des animaux traités. Ces résultats précliniques ouvrent la voie à un essai thérapeutique chez l'enfant atteint de dystrophie musculaire de Duchenne

Nematode dermatitis due to Angiostrongylus vasorum infection in a dog

BACKGROUND: Angiostrongylus vasorum is a nematode that primarily infects Canidae. The adult parasites are found in the pulmonary arterial circulation and the right side of the heart. The most common clinical sign is respiratory dysfunction. Bleeding, neurological, ocular, cardiovascular and gastrointestinal disorders are also reported. Skin lesions are very unusual. HYPOTHESIS/OBJECTIVES: This report describes a nematode dermatitis due to A. vasorum infection. To the best of the authors' knowledge, this is the first case of a dog infected with this parasite that initially presented with skin lesions only. ANIMAL: A 3-year-old female Weimaraner dog presented with a crusted papular dermatitis on the bridge of the nose and on the pinnae, and an erythematous pododermatitis with erosions and perionyxis of one digit of 1 week's duration. Two weeks later the dog developed respiratory distress. METHODS AND RESULTS: Skin scrapings and fungal culture were negative for parasites and dermatophytes. Histopathological examination showed dermal granulomas and pyogranulomas with eosinophils centred around parasitic elements compatible with nematode larvae. Angiostrongylus vasorum DNA was demonstrated in skin biopsies. Chest radiographs were compatible with verminous pneumonia and a Baermann test revealed A. vasorum larvae. The dog was treated orally with fenbendazole, with rapid improvement and complete cure after 3 months. CONCLUSIONS AND CLINICAL IMPORTANCE: Angiostrongylus vasorum should be considered in dogs presented with skin lesions and respiratory signs. Skin biopsy, chest radiographs and Baermann test should be included in the diagnostic investigation

NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis

Sterile liver inflammation and fibrosis are associated with many liver disorders of different etiologies. Both type 1 and type 2 inflammatory responses have been reported to contribute to liver pathology. However, the mechanisms controlling the balance between these responses are largely unknown. Natural killer T (NKT) cells can be activated to rapidly secrete cytokines and chemokines associated with both type 1 and type 2 inflammatory responses. As these proteins have been reported to accumulate in different types of sterile liver inflammation, we hypothesized that these cells may play a role in this pathological process. We have found that a transgenic NKT (tgNKT) cell population produced in the immunodeficient 2,4αβNOD.Rag2−/− mice, but not in  2,4αβNOD.Rag2+/− control mice, promoted a type 1 inflammatory response with engagement of the NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome. The induction of the type 1 inflammatory response was followed by an altered cytokine profile of the tgNKT cell population with a biased production of anti-inflammatory/profibrotic cytokines and development of liver fibrosis. These findings illustrate how the plasticity of NKT cells modulates the inflammatory response, suggesting a key role for the NKT cell population in the control of sterile liver inflammation

Systemic delivery of allogenic muscle stem cells induces long-term muscle repair and clinical efficacy in duchenne muscular dystrophy dogs.

Muscle Stem = MuStemInternational audienceDuchenne muscular dystrophy (DMD) is a genetic progressive muscle disease resulting from the lack of dystrophin and without effective treatment. Adult stem cell populations have given new impetus to cell-based therapy of neuromuscular diseases. One of them, muscle-derived stem cells, isolated based on delayed adhesion properties, contributes to injured muscle repair. However, these data were collected in dystrophic mice that exhibit a relatively mild tissue phenotype and clinical features of DMD patients. Here, we characterized canine delayed adherent stem cells and investigated the efficacy of their systemic delivery in the clinically relevant DMD animal model to assess potential therapeutic application in humans. Delayed adherent stem cells, named MuStem cells (muscle stem cells), were isolated from healthy dog muscle using a preplating technique. In vitro, MuStem cells displayed a large expansion capacity, an ability to proliferate in suspension, and a multilineage differentiation potential. Phenotypically, they corresponded to early myogenic progenitors and uncommitted cells. When injected in immunosuppressed dystrophic dogs, they contributed to myofiber regeneration, satellite cell replenishment, and dystrophin expression. Importantly, their systemic delivery resulted in long-term dystrophin expression, muscle damage course limitation with an increased regeneration activity and an interstitial expansion restriction, and persisting stabilization of the dog's clinical status. These results demonstrate that MuStem cells could provide an attractive therapeutic avenue for DMD patients

Skeletal Clinical improvement and skeletal muscle repair in GRMD dogs, after allogenic muscle Stem (MuStem) cell systemic delivery.

Skeletal Clinical improvement and skeletal muscle repair in GRMD dogs, after allogenic muscle Stem (MuStem) cell systemic delivery.. Combined Meeting of the 17th ESGCT/16th German Society for Gene Therapy/4th German Society for Stem Cell Researc