Rebuttal to: Simvastatin Treatment Does Not Ameliorate Muscle Pathophysiology in a Mouse Model for Duchenne Muscular Dystrophy, Verhaart et al. 2020

Abstract Background: Duchenne muscular dystrophy (DMD) is an incurable disease, caused by the mutations in the DMD gene, encoding dystrophin, an actin-binding cytoskeletal protein. Lack of functional dystrophin results in muscle weakness, degeneration, and as an outcome cardiac and respiratory failure. As there is still no cure for affected individuals, the pharmacological compounds with the potential to treat or at least attenuate the symptoms of the disease are under constant evaluation. The pleiotropic agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, known as statins, have been suggested to exert beneficial effects in the mouse model of DMD. On the other hand, they were also reported to induce skeletal-muscle myopathy.Methods: Several methods including functional assessment of muscle function via grip strength measurement and treadmill test, enzymatic assays, histological analysis of muscle damage, gene expression evaluation, and immunofluorescence staining were conducted to study simvastatin-related alterations in mdx mice.Results: In our study, simvastatin treatment of mdx mice did not result in improved running performance; however, some beneficial effect was observed when grip strength was evaluated. Creatine kinase and lactate dehydrogenase activity, markers of muscle injury, were diminished after simvastatin delivery in mdx mice. Nevertheless, no significant changes in inflammation, fibrosis, and necrosis were noted. Interestingly, simvastatin treatment led to the decreased mRNA level of embryonic myosin heavy chain isoform, a declined percentage of centrally nucleated myofibers, and miR-1 upregulation, suggesting an alteration in the muscle regeneration. However, similarly to the changes noticed in the expression of some angiogenic factors, the obtained results are muscle-dependent, being prominent in gastrocnemius muscle but not in the diaphragm.Conclusion: In conclusion, we suggest that simvastatin has the potential to ameliorate selected aspects of DMD pathology; however, possible benefits still need to be thoroughly tested.

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Faculty Opinions recommendation of Bi-specific splice-switching PMO oligonucleotides conjugated via a single peptide active in a mouse model of Duchenne muscular dystrophy.

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

10.3410/f.725255143.793521792 ◽

2016 ◽

Author(s):

George Dickson

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Single Peptide

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VEGFR-1/Flt-1 Inhibition Increases Angiogenesis and Improves Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy

Molecular Therapy — Methods & Clinical Development ◽

10.1016/j.omtm.2021.03.013 ◽

2021 ◽

Author(s):

Jennifer Bosco ◽

Zhiwei Zhou ◽

Sofie Gabriëls ◽

Mayank Verma ◽

Nan Liu ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Muscle Function

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TENASCIN C PROMOTES ENDOTHELIAL DYSFUNCTION ACCOMPANIED WITH CARDIAC FIBROSIS IN A MOUSE MODEL OF DUCHENNE MUSCULAR DYSTROPHY

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(21)02200-2 ◽

2021 ◽

Vol 77 (18) ◽

pp. 841

Author(s):

Petra Lujza Szabo ◽

Ouafa Hamza ◽

Milat Inci ◽

Janine Ebner ◽

Karlheinz Hilber ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Endothelial Dysfunction ◽

Muscular Dystrophy ◽

Mouse Model ◽

Cardiac Fibrosis ◽

Tenascin C

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In vivo genome editing in mouse restores dystrophin expression in Duchenne muscular dystrophy patient muscle fibers

Genome Medicine ◽

10.1186/s13073-021-00876-0 ◽

2021 ◽

Vol 13 (1) ◽

Cited By ~ 1

Author(s):

Menglong Chen ◽

Hui Shi ◽

Shixue Gou ◽

Xiaomin Wang ◽

Lei Li ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Genome Editing ◽

Large Scale ◽

Gene Editing ◽

High Efficiency ◽

Muscle Fibers ◽

Muscle Cells

Abstract Background Mutations in the DMD gene encoding dystrophin—a critical structural element in muscle cells—cause Duchenne muscular dystrophy (DMD), which is the most common fatal genetic disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing is a promising strategy for permanently curing DMD. Methods In this study, we developed a novel strategy for reframing DMD mutations via CRISPR-mediated large-scale excision of exons 46–54. We compared this approach with other DMD rescue strategies by using DMD patient-derived primary muscle-derived stem cells (DMD-MDSCs). Furthermore, a patient-derived xenograft (PDX) DMD mouse model was established by transplanting DMD-MDSCs into immunodeficient mice. CRISPR gene editing components were intramuscularly delivered into the mouse model by adeno-associated virus vectors. Results Results demonstrated that the large-scale excision of mutant DMD exons showed high efficiency in restoring dystrophin protein expression. We also confirmed that CRISPR from Prevotella and Francisella 1(Cas12a)-mediated genome editing could correct DMD mutation with the same efficiency as CRISPR-associated protein 9 (Cas9). In addition, more than 10% human DMD muscle fibers expressed dystrophin in the PDX DMD mouse model after treated by the large-scale excision strategies. The restored dystrophin in vivo was functional as demonstrated by the expression of the dystrophin glycoprotein complex member β-dystroglycan. Conclusions We demonstrated that the clinically relevant CRISPR/Cas9 could restore dystrophin in human muscle cells in vivo in the PDX DMD mouse model. This study demonstrated an approach for the application of gene therapy to other genetic diseases.

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