Laminin-111 protein therapy enhances muscle regeneration and repair in the GRMD dog model of Duchenne muscular dystrophy

Abstract Duchenne muscular dystrophy (DMD) is a devastating X-linked disease affecting ~1 in 5000 males. DMD patients exhibit progressive muscle degeneration and weakness, leading to loss of ambulation and premature death from cardiopulmonary failure. We previously reported that mouse Laminin-111 (msLam-111) protein could reduce muscle pathology and improve muscle function in the mdx mouse model for DMD. In this study, we examined the ability of msLam-111 to prevent muscle disease progression in the golden retriever muscular dystrophy (GRMD) dog model of DMD. The msLam-111 protein was injected into the cranial tibial muscle compartment of GRMD dogs and muscle strength and pathology were assessed. The results showed that msLam-111 treatment increased muscle fiber regeneration and repair with improved muscle strength and reduced muscle fibrosis in the GRMD model. Together, these findings support the idea that Laminin-111 could serve as a novel protein therapy for the treatment of DMD.

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Correction for Rooney et al., Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0908571106 ◽

2009 ◽

Vol 106 (36) ◽

pp. 15514-15514 ◽

Cited By ~ 1

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Muscle Disease ◽

Mdx Mouse ◽

Protein Therapy

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Faculty Opinions recommendation of Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1160742.622147 ◽

2009 ◽

Author(s):

Markus Ruegg

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Muscle Disease ◽

Mdx Mouse ◽

Protein Therapy

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Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0811599106 ◽

2009 ◽

Vol 106 (19) ◽

pp. 7991-7996 ◽

Cited By ~ 82

Author(s):

J. E. Rooney ◽

P. B. Gurpur ◽

D. J. Burkin

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Muscle Disease ◽

Mdx Mouse ◽

Protein Therapy

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P4.24 Glatiramer acetate (Copaxone) decreases macrophage infiltration and increases muscle strength in mdx mouse model of Duchenne muscular dystrophy

Neuromuscular Disorders ◽

10.1016/j.nmd.2011.06.989 ◽

2011 ◽

Vol 21 (9-10) ◽

pp. 711

Author(s):

Z. Brunschwig ◽

N. Yanay ◽

S. Aga-Mizrachi ◽

K. Ettinger ◽

M. Elbaz ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Strength ◽

Mouse Model ◽

Glatiramer Acetate ◽

Macrophage Infiltration ◽

Mdx Mouse

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238 TAILORED PIG MODEL OF DUCHENNE MUSCULAR DYSTROPHY

Reproduction Fertility and Development ◽

10.1071/rdv24n1ab238 ◽

2012 ◽

Vol 24 (1) ◽

pp. 231 ◽

Cited By ~ 2

Author(s):

N. Klymiuk ◽

C. Thirion ◽

K. Burkhardt ◽

A. Wuensch ◽

S. Krause ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Nuclear Transfer ◽

Muscle Disease ◽

Pig Model ◽

Mdx Mouse ◽

Cell Clones ◽

Fatty Replacement ◽

Dmd Gene ◽

Dystrophin Protein

Duchenne muscular dystrophy (DMD) is one of the most common genetic diseases in humans, affecting 1 in 3500 boys. It is characterised by progressive muscle weakness and wasting due to mutations in the dystrophin (DMD) gene resulting in absence of dystrophin protein in skeletal muscle. Although curative treatments are currently not available, genetic and pharmacological approaches are under investigation including early-phase clinical trials. Existing animal models in different species (e.g. mdx mouse, GRMD dog) have been instrumental to understand the pathophysiology of DMD, but have several limitations. Importantly, the causative point mutations (mdx mouse: nonsense mutation; GRMD dog: splice mutation) are different from the most common human mutations (out-of-frame deletion of one or several exons of the DMD gene). We used gene targeting in somatic cells and nuclear transfer to generate a genetically tailored pig model of DMD. A bacterial artificial chromosome (BAC) from the porcine DMD gene was modified by recombineering to replace exon 52, resulting in a frame shift in the transcript. Modified BAC were transfected into male neonatal kidney cells, which were screened by quantitative polymerase chain reaction for replacement of exon 52 in the X-linked DMD gene. Eight of 436 cell clones were successfully targeted and 2 of them were used for nuclear transfer. For each of the cell clones, a pregnancy was established by transfer of cloned embryos into recipient gilts. Four piglets of the first litter were live born and killed within 48 h and tissue samples were processed for histological characterisation. Two piglets of the second litter died during birth due to obstetric complications, whereas the other 2 piglets were delivered by Caesarean section and raised in an artificial feeding system. Their serum creatine kinase (CK) levels were grossly elevated. Although both piglets showed reduced mobility compared with age-matched controls, they were able to move and feed on their own. Immunofluorescence staining of dystrophin was negative in muscle fibres of DMD mutant piglets and the complete absence of dystrophin protein was confirmed by immunoblot analysis. Histological examination of biceps femoris muscle from DMD mutant pigs showed a degenerative myopathy with fibre size variation, rounded fibres, central nuclei, fibrosis and fatty replacement of muscle tissue mimicking the hallmarks of the human disease. In conclusion, we generated the first pig model for a genetic muscle disease. The DMD mutant pig appears to be a bona fide model of the human dystrophy as ascertained by absence of the dystrophin protein, elevated serum CK levels and early degenerative changes on muscle histology. Because deletion of exon 52 is one of the most frequent mutations found in human DMD, the exon 52 mutated DMD pig represents an excellent model for testing targeted genetic treatments. This study was supported by the Bayerische Forschungsstiftung.

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Increased plasma lipid levels exacerbate muscle pathology in the mdx mouse model of Duchenne muscular dystrophy

Skeletal Muscle ◽

10.1186/s13395-017-0135-9 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 15

Author(s):

Nadia Milad ◽

Zoe White ◽

Arash Y. Tehrani ◽

Stephanie Sellers ◽

Fabio M.V. Rossi ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Plasma Lipid ◽

Muscle Pathology ◽

Mdx Mouse ◽

Lipid Levels

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Validation of Chemokine Biomarkers in Duchenne Muscular Dystrophy

Life ◽

10.3390/life11080827 ◽

2021 ◽

Vol 11 (8) ◽

pp. 827

Author(s):

Michael Ogundele ◽

Jesslyn S. Zhang ◽

Mansi V. Goswami ◽

Marissa L. Barbieri ◽

Utkarsh J. Dang ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Early Stage ◽

Wild Type Mouse ◽

Muscle Disease ◽

Mdx Mouse ◽

Control Group ◽

P Value ◽

Glucocorticoid Treatment

Duchenne muscular dystrophy (DMD) is a progressive muscle disease involving complex skeletal muscle pathogenesis. The pathogenesis is triggered by sarcolemma instability due to the lack of dystrophin protein expression, leading to Ca2+ influx, muscle fiber apoptosis, inflammation, muscle necrosis, and fibrosis. Our lab recently used two high-throughput multiplexing techniques (e.g., SomaScan® aptamer assay and tandem mass tag-(TMT) approach) and identified a series of serum protein biomarkers tied to different pathobiochemical pathways. In this study, we focused on validating the circulating levels of three proinflammatory chemokines (CCL2, CXCL10, and CCL18) that are believed to be involved in an early stage of muscle pathogenesis. We used highly specific and reproducible MSD ELISA assays and examined the association of these chemokines with DMD pathogenesis, age, disease severity, and response to glucocorticoid treatment. As expected, we confirmed that these three chemokines were significantly elevated in serum and muscle samples of DMD patients relative to age-matched healthy controls (p-value < 0.05, CCL18 was not significantly altered in muscle samples). These three chemokines were not significantly elevated in Becker muscular dystrophy (BMD) patients, a milder form of dystrophinopathy, when compared in a one-way ANOVA to a control group but remained significantly elevated in the age-matched DMD group (p < 0.05). CCL2 and CCL18 but not CXCL10 declined with age in DMD patients, whereas all three chemokines remained unchanged with age in BMD and controls. Only CCL2 showed significant association with time to climb four steps in the DMD group (r = 0.48, p = 0.038) and neared significant association with patients’ reported outcome in the BMD group (r = 0.39, p = 0.058). Furthermore, CCL2 was found to be elevated in a serum of the mdx mouse model of DMD, relative to wild-type mouse model. This study suggests that CCL2 might be a suitable candidate biomarker for follow-up studies to demonstrate its physiological significance and clinical utility in DMD.

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