Laminin-deficient muscular dystrophy: Molecular pathogenesis and structural repair strategies

Yurchenco, Peter D.; McKee, Karen K.; Reinhard, Judith; Rüegg, Markus A.

doi:10.1016/j.matbio.2017.11.009

Cited by 91 publications

(104 citation statements)

References 112 publications

(127 reference statements)

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“…Despite significant development of successful genetic and pharmacological preclinical treatment strategies in mice there is still no cure for LAMA2-CMD, the second-most common form of congenital muscular dystrophy [1,38,39]. We here demonstrate increased ROS production in LAMA2-CMD mouse and patient skeletal muscle.…”

Section: Discussionmentioning

confidence: 56%

Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy

et al. 2020

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Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe neuromuscular disorder without a cure. Using transcriptome and proteome profiling as well as functional assays, we previously demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Reactive oxygen species (ROS) increase when oxygen homeostasis is not maintained and, here, we investigate whether oxidative stress indeed is involved in the pathogenesis of LAMA2-CMD. We also analyze the effects of two antioxidant molecules, N-acetyl-L-cysteine (NAC) and vitamin E, on disease progression in the dy 2J /dy 2J mouse model of LAMA2-CMD. We demonstrate increased ROS levels in LAMA2-CMD mouse and patient skeletal muscle. Furthermore, NAC treatment (150 mg/kg IP for 6 days/week for 3 weeks) led to muscle force loss prevention, reduced central nucleation and decreased the occurrence of apoptosis, inflammation, fibrosis and oxidative stress in LAMA2-CMD muscle. In addition, vitamin E (40 mg/kg oral gavage for 6 days/week for 2 weeks) improved morphological features and reduced inflammation and ROS levels in dy 2J /dy 2J skeletal muscle. We suggest that NAC and to some extent vitamin E might be potential future supportive treatments for LAMA2-CMD as they improve numerous pathological hallmarks of LAMA2-CMD.

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Section: Discussionmentioning

confidence: 56%

Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy

et al. 2020

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“…The three most commonly used animal models for LAMA2-CMD are dy 2J /dy 2J (Xu et al, 1994b;Sunada et al, 1995), dy 3K /dy 3K (Miyagoe et al, 1997), and dy W /dy W mice (Kuang et al, 1998b; Table 1 and Figure 1). Skeletal muscle and peripheral nerve are the tissues with the most evident pathology in LAMA2-CMD mutants (Yurchenco et al, 2017). The dystrophic symptoms and general muscle pathology at the advanced stages of the disease have been fairly well characterized in all three models (Xu et al, 1994b;Miyagoe et al, 1997;Kuang et al, 1998b;Moll et al, 2001;Guo et al, 2003;Girgenrath et al, 2004Girgenrath et al, , 2009Gawlik et al, , 2018Carmignac et al, 2011a;Kumar et al, 2011;Pasteuning-Vuhman et al, 2018).…”

Section: Overview Of Lama2-cmd Mouse Modelsmentioning

confidence: 99%

“…It is important to mention that peripheral nerve defects cause neurogenic atrophy of muscle fibers (Gawlik et al, 2004;McKee et al, 2012) and contribute to dystrophic phenotype of skeletal muscle. Interestingly, although peripheral neuropathy is pronounced in all LAMA2-CMD mouse models (Guo et al, 2003), it is rarely manifested in patients (Yurchenco et al, 2017). Respiratory function in dy 2J /dy 2J mice has been assessed with the whole-body plethysmography.…”

Section: Phenotype Of Dy 2j /Dy 2j Micementioning

confidence: 99%

A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

Gawlik

Durbeej

2020

Front. Mol. Neurosci.

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The research on laminin α2 chain-deficient congenital muscular dystrophy (LAMA2-CMD) advanced rapidly in the last few decades, largely due to availability of good mouse models for the disease and a strong interest in preclinical studies from scientists all over the world. These mouse models continue to provide a solid platform for understanding the LAMA2-CMD pathology. In addition, they enable researchers to test laborious, necessary routines, but also the most creative scientific approaches in order to design therapy for this devastating disorder. In this review we present animals belonging to the laminin α2 chain-deficient "dy/dy" mouse family (dy/dy, dy 2J /dy 2J , dy 3K /dy 3K , dy W /dy W , et al.) and a summary of the scientific progress they facilitated. We also raise a few questions that need to be addressed in order to maximize the usefulness of laminin α2 murine mutants and to further advance the LAMA2-CMD studies. We believe that research opportunities offered by the mouse models for LAMA2-CMD will continuously support our efforts to find a treatment for the disease.

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“…VP64-dCas9, VP64-dCas9 sgRNA 1 and VP64-dCas9 sgRNA 123 plasmids were packaged into AAV9 vectors by Vigene Biosciences as previously described 3 . Injection solutions were comprised of either 7.5x10 11 , 1.5x10 12 or 3.0x10 12 viral genome/AAV9…”

Section: Engineering Of Activation S Aureus Dcas9 Cloning and Virusmentioning

confidence: 99%

“…RNA was isolated from cultured cells and mouse tissue sections, and cDNA synthesis was performed as previously described 3 . PCR amplification was utilized to assess the efficiency of each guide in upregulating Lama1 expression using a primer in Lama1 exon 55 (RDC 1919) and a second primer spanning the junction of exons 55 and 56 (RDC 1920).…”

Section: Rna Isolation Guide Screening and Rt-pcrmentioning

confidence: 99%

A mutation-independent approach via transcriptional upregulation of a disease modifier gene rescues muscular dystrophy in vivo

Kemaladewi

Lindsay

et al. 2018

Preprint

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Introductory paragraphIdentification of protective and/or pathogenic genetic modifiers provides important insight into the heterogeneity of disease presentations in individuals affected by neuromuscular disorders (NMDs), despite having well-defined pathogenic variants. Targeting modifier genes to improve disease phenotypes could be especially beneficial in cases where the causative genes are large, structurally complex and the mutations are heterogeneous. Here, we report a mutation-independent strategy to upregulate expression of a compensatory disease-modifying gene in Congenital Muscular Dystrophy type 1A (MDC1A) using a CRISPR/dCas9-based transcriptional activation system. MDC1A is caused by nonfunctional Laminin α2, which compromises muscle fibers stability and axon myelination in peripheral nerves 1. Transgenic overexpression of Lama1, encoding a structurally similar protein Laminin α1, ameliorates muscle wasting and paralysis in the MDC1A mouse models, demonstrating its role as a protective disease modifier 2. Yet, upregulation of Lama1 as a postnatal gene therapy is hampered by its large size, which exceeds the current genome packaging capacity of clinically relevant delivery vehicles such as adeno-associated viral vectors (AAVs). In this study, we sought to upregulate Lama1 using CRISPR/dCas9-based transcriptional activation system, comprised of catalytically inactive S. aureus Cas9 (dCas9) fused to VP64 transactivation domains and sgRNAs targeting the Lama1 promoter. We first demonstrated robust upregulation of Lama1 in myoblasts, and following AAV9-mediated intramuscular delivery, in skeletal muscles of dy2j/dy2j mouse model of MDC1A.We therefore assessed whether systemic upregulation of Lama1 would yield therapeutic benefits in dy2j/dy2j mice. When the intervention was started early in pre-symptomatic dy2j/dy2j mice, Lama1 upregulation prevented muscle fibrosis and hindlimb paralysis. An important question for future therapeutic approaches for a variety of disorders concerns the therapeutic window and phenotypic reversibility. This is particularly true for muscular dystrophies as it has long been hypothesized that fibrotic changes in skeletal muscle represent an irreversible disease state that would impair any therapeutic intervention at advanced stages of the disease. Here, we demonstrate that dystrophic features and disease progression were significantly improved and partially reversed when the treatment was initiated in symptomatic 3-week old dy2j/dy2j mice with already-apparent hind limb paralysis and significant muscle fibrosis.Collectively, our data demonstrate the feasibility and therapeutic benefit of CRISPR/dCas9-mediated modulation of a disease modifier gene, which opens up an entirely new and mutation-independent treatment approach for all MDC1A patients. Moreover, this treatment strategy provides evidence that muscle fibrosis can be reversible, thus extending the therapeutic window for this disorder. Our data provide a proof-of-concept strategy that can be applied to a variety of disease modifier genes and a powerful therapeutic approach for various inherited and acquired diseases.

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Laminin-deficient muscular dystrophy: Molecular pathogenesis and structural repair strategies

Cited by 91 publications

References 112 publications

Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy

Antioxidants Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy

A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

A mutation-independent approach via transcriptional upregulation of a disease modifier gene rescues muscular dystrophy in vivo

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