scholarly journals Laminin-111 Protein Therapy Reduces Muscle Pathology and Improves Viability of a Mouse Model of Merosin-Deficient Congenital Muscular Dystrophy

2012 ◽  
Vol 180 (4) ◽  
pp. 1593-1602 ◽  
Author(s):  
Jachinta E. Rooney ◽  
Jolie R. Knapp ◽  
Bradley L. Hodges ◽  
Ryan D. Wuebbles ◽  
Dean J. Burkin
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Congenital Muscular Dystrophy ◽  
Muscle Pathology ◽  
Protein Therapy

scholarly journals Laminin-111 protein therapy after disease onset slows muscle disease in a mouse model of laminin-α2 related congenital muscular dystrophy

2020 ◽  
Vol 29 (13) ◽  
pp. 2162-2170
Author(s):  
Pamela Barraza-Flores ◽  
Katherine E Bukovec ◽  
Marisela Dagda ◽  
Brandon W Conner ◽  
Ariany Oliveira-Santos ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Life Expectancy ◽  
Mouse Model ◽  
Replacement Therapy ◽  
Disease Onset ◽  
Congenital Muscular Dystrophy ◽  
Muscle Disease ◽  
Muscle Pathology ◽  
Protein Therapy ◽  
Laminin Α2

Abstract Laminin-α2 related congenital muscular dystrophy (LAMA2-CMD) is a fatal muscle disease caused by mutations in the LAMA2 gene. Laminin-α2 is critical for the formation of laminin-211 and -221 heterotrimers in the muscle basal lamina. LAMA2-CMD patients exhibit hypotonia from birth and progressive muscle loss that results in developmental delay, confinement to a wheelchair, respiratory insufficiency and premature death. There is currently no cure or effective treatment for LAMA2-CMD. Several studies have shown laminin-111 can serve as an effective protein-replacement therapy for LAMA2-CMD. Studies have demonstrated early treatment with laminin-111 protein results in an increase in life expectancy and improvements in muscle pathology and function. Since LAMA2-CMD patients are often diagnosed after advanced disease, it is unclear if laminin-111 protein therapy at an advanced stage of the disease can have beneficial outcomes. In this study, we tested the efficacy of laminin-111 protein therapy after disease onset in a mouse model of LAMA2-CMD. Our results showed laminin-111 treatment after muscle disease onset increased life expectancy, promoted muscle growth and increased muscle stiffness. Together these studies indicate laminin-111 protein therapy either early or late in the disease process could serve as an effective protein replacement therapy for LAMA2-CMD.

scholarly journals Early skeletal muscle pathology and disease progress in the dy3K/dy3K mouse model of congenital muscular dystrophy with laminin α2 chain-deficiency

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kinga I. Gawlik ◽  
Zandra Körner ◽  
Bruno M. Oliveira ◽  
Madeleine Durbeej
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Congenital Muscular Dystrophy ◽  
Masticatory Muscles ◽  
Severe Form ◽  
Matrix Proteins ◽  
Muscle Pathology ◽  
Muscle Fibres ◽  
Disease Initiation ◽  
Laminin Α2

Abstract Deficiency of laminin α2 chain leads to a severe form of congenital muscular dystrophy (LAMA2-CMD), and dystrophic symptoms progress rapidly in early childhood. Currently, there is no treatment for this detrimental disorder. Development of therapies is largely hindered by lack of understanding of mechanisms involved in the disease initiation and progress, both in patients but also in mouse models that are commonly used in the preclinical setup. Here, we unveil the first pathogenic events and characterise the disease development in a mouse model for LAMA2-CMD (dy3K/dy3K), by analysing muscles at perinatal, neonatal and postnatal stages. We found that apoptotic muscle fibres were present as early as postnatal day 1. Other typical dystrophic hallmarks (muscle degeneration, inflammation, and extensive production of the extracellular matrix proteins) were clearly evident already at postnatal day 4, and the highest degree of muscle deterioration was reached by day 7. Interestingly, the severe phenotype of limb muscles partially recovered on days 14 and 21, despite worsening of the general condition of the dy3K/dy3K mouse by that age. We found that masticatory muscles were severely affected in dy3K/dy3K mice and this may be an underlying cause of their malnutrition, which contributes to death around day 21. We also showed that several signalling pathways were affected already in 1-day-old dy3K/dy3K muscle. Therapeutic tests in the dy3K/dy3K mouse model should therefore be initiated shortly after birth, but should also take into account timing and correlation between regenerative and pathogenic events.

scholarly journals Improving Reproducibility of Phenotypic Assessments in the DyW Mouse Model of Laminin-α2 Related Congenital Muscular Dystrophy

2017 ◽  
Vol 4 (2) ◽  
pp. 115-126 ◽  
Author(s):  
Raffaella Willmann ◽  
Heather Gordish-Dressman ◽  
Sarina Meinen ◽  
Markus A. Rüegg ◽  
Qing Yu ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Congenital Muscular Dystrophy ◽  
Laminin Α2

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

2019 ◽  
Vol 28 (16) ◽  
pp. 2686-2695 ◽  
Author(s):  
Pamela Barraza-Flores ◽  
Tatiana M Fontelonga ◽  
Ryan D Wuebbles ◽  
Hailey J Hermann ◽  
Andreia M Nunes ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Strength ◽  
Premature Death ◽  
Muscle Disease ◽  
Muscle Pathology ◽  
Mdx Mouse ◽  
Protein Therapy ◽  
Muscle Fibrosis ◽  
Dog Model

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.

scholarly journals Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G

2019 ◽  
Vol 5 (2) ◽  
pp. e315 ◽  
Author(s):  
Angela J. Lee ◽  
Karra A. Jones ◽  
Russell J. Butterfield ◽  
Mary O. Cox ◽  
Chamindra G. Konersman ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Founder Mutation ◽  
Congenital Muscular Dystrophy ◽  
Clinical Severity ◽  
Muscle Pathology ◽  
Clinical Genetic ◽  
End Stage ◽  
Muscle Biopsies ◽  
Normal Cognition

ObjectiveTo characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the FKRP c.1387A>G mutation.MethodsStandardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in FKRP. Muscle biopsies were reviewed and used for histopathology, immunostaining, Western blotting, and DNA extraction. Genetic analysis was performed on extracted DNA.ResultsWe report the clinical phenotypes of 6 patients homozygous for the c.1387A>G mutation in FKRP. Onset of symptoms was <2 years, and 5 of the 6 patients never learned to walk. Brain MRIs were normal. Cognition was normal to mildly impaired. Microarray analysis of 5 homozygous FKRP c.1387A>G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including FKRP. All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated α-dystroglycan (α-DG) by immunofluorescence, and reduced molecular weight of α-DG compared with controls and patients with homozygous FKRP c.826C>A limb-girdle muscular dystrophy.ConclusionsThe clinical features and muscle pathology in these newly reported patients homozygous for FKRP c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that FKRP c.1387A>G is a founder mutation with an estimated age of 60 generations (∼1,200–1,500 years).

scholarly journals A modified diet does not ameliorate muscle pathology in a mouse model for Duchenne muscular dystrophy

PLoS ONE ◽  
2019 ◽  
Vol 14 (4) ◽  
pp. e0215335
Author(s):  
Ingrid E. C. Verhaart ◽  
Davy van de Vijver ◽  
Joke W. Boertje-van der Meulen ◽  
Kayleigh Putker ◽  
Kevin Adamzek ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Muscle Pathology ◽  
Modified Diet
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