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Zekr and luther muscle fanfiction5/10/2023 ![]() We thus discuss ethical issues, emphasizing that unlike many other models, the dog also benefits from its contribution to comparative biomedical research with a drastic reduction in the prevalence of morbid alleles in the breeding stock and an improvement in medical care. Because the dog is one of the most protected research animal models, there is considerable opposition to include it in preclinical projects, posing a threat to the use of this model. ![]() This review also contextualizes the model by highlighting its unique genetic value, shaped by the long-term coevolution of humans and domesticated dogs. This toolbox offers scientists a sensitive and reliable system to thoroughly evaluate neuromuscular function, as well as efficiency and safety of innovative therapies targeting these NMDs. Finally, interindividual phenotypic heterogeneity between dogs helps identifying modifiers and anticipates precision medicine issues.This review article summarizes the present list of molecularly characterized dog models for NMDs and provides an exhaustive list of the clinical and paraclinical assays that have been developed. Moreover, the highly similar pathogenic mechanisms with human patients yield to translational robustness. Dogs' characteristics including size, lifespan and unprecedented medical care level allow a comprehensive longitudinal description of diseases. The continuous emergence of spontaneous inherited disorders enables the identification of reliable complementary molecular models for human neuromuscular disorders (NMDs). Mostly, this is due to unique features that make dogs an optimal system. A recent example of the utility of this animal model is the promising myotubularin gene delivery in boys affected by X-linked centronuclear myopathy after successful systemic, long-term efficient gene therapy in Labrador retrievers. Asterisks indicate P = 0.05 (*), P <0.01 (**), P <0.001 (***).ĭogs have long been used as a biomedical model system and in particular as a preclinical proof of concept for innovative therapies before translation to humans. Data are expressed as percentage of marker expression per total area. For all panels, muscle sections (3 per muscle) were either immunostained with the macrophage marker, F4/80, to measure inflammation, or incubated with a fluorescent conjugated immunoglobin (IgG) to assess necrosis, or stained with the embryonic form of myosin heavy chain (eMyHC) to detect regenerative myofibers. Quad muscles were analyzed from NBD and vehicle treated mice (n = 5 per group). (C)Mdx mice were treated with vehicle or NBD (10 mg/kg) 3× weekly, by IV delivery for a period of 4 weeks. Quad muscles were analyzed from NBD and vehicle treated mdx mice (n = 10 per group). ![]() (B)Mdx mice were treated with vehicle or NBD (10 mg/kg), 3× weekly, by SQ delivery, for a period of 4 weeks. Quadriceps (Quad) muscles were selected as a representative hind limb muscle from NBD treated mdx mice (n = 5 per group). (A)Mdx mice were treated by IP delivery for a period of 4 weeks with NBD (10 mg/kg) for either 3 days (d), 2 days, or 1 day per week. This GRMD trial was beneficial both in providing evidence that NBD is efficacious in a large animal DMD model and in identifying potential safety concerns that will be informative moving forward with human trials.Įstablishing a delivery and dosing schedule for NBD in mdx mice. Despite this phenotypic improvement, NBD administration over time led to infusion reactions and an immune response in both treated GRMD and wild type dogs. In addition, NBD-treated GRMD dogs had normalized postural changes and a trend towards lower tissue injury on magnetic resonance imaging. Results showed that intravenous delivery of NBD in GRMD dogs led to a recovery of pelvic limb muscle force and improvement of histopathologic lesions. Results were compared with those collected from untreated GRMD and wild type dogs through a separate, natural history study. GRMD and wild type dogs at 2 months of age were treated for 4 months with NBD by intravenous infusions. Previous studies showed that DMD is associated with constitutive activation of NF-κB, and in dystrophin-deficient mdx and utrophin/dystrophin (utrn (-/-) mdx) double knock out (dko) mouse models, inhibition of NF-κB with the Nemo Binding Domain (NBD) peptide led to significant improvements in both diaphragm and cardiac muscle function.Ī trial in golden retriever muscular dystrophy (GRMD) canine model of DMD was initiated with four primary outcomes: skeletal muscle function, MRI of pelvic limb muscles, histopathologic features of skeletal muscles, and safety. Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and afflicts skeletal and cardiac muscles.
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