====== Duchenne muscular dystrophy ======

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The most common [[muscular dystrophy]] is Duchenne muscular [[dystrophy]] (DMD), which typically affects [[male]]s beginning around the age of four.

It is a degenerative, lethal, X-linked disease of skeletal and [[cardiomyopathy]] caused by mutations in the dystrophin gene. 

===== Treatment =====

[[Cell therapy]] using different cell types, including [[mesenchymal stromal cell]]s (MSCs), has been considered as a potential approach for the treatment of DMD. 

MSCs can be obtained from autologous sources such as [[bone marrow]] and [[adipose tissue]]s or from allogeneic [[placenta]] and [[umbilical cord]]. 

The safety and therapeutic impact of these cells has been demonstrated in pre-clinical and clinical studies and their functions are attributed to paracrine effects that are mediated by secreted [[cytokine]]s and extracellular vesicles. 

Bier et al., studied the therapeutic effects of placenta-derived MSCs (PL-MSCs) and their secreted [[exosome]]s using [[mouse]] and human [[myoblast]]s from healthy controls, Duchenne patients and mdx mice. Treatment of myoblasts with conditioned medium or exosomes secreted by PL-MSCs increased the differentiation of these cells and decreased the expression of fibrogenic genes in DMD patient myoblasts. In addition, these treatments also increased the expression of utrophin in these cells. 

Using a quantitative [[miR 29c]] reporter, Bier et al., demonstrated that the PL-[[MSC]] effects were partly mediated by the transfer of exosomal miR-29c. Intramuscular transplantation of PL-MSCs in mdx mice resulted in decreased creatine kinase levels. PL-MSCs significantly decreased the expression of [[TGF]]-β and the level of [[fibrosis]] in the diaphragm and cardiac muscles, inhibited inflammation and increased utrophin expression. In vivo imaging analyses using MSCs labeled with gold [[nanoparticle]]s or fluorescent dyes demonstrated localization of the cells in the muscle tissues up to 3 weeks post treatment. Altogether, these results demonstrate that PL-MSCs and their secreted exosomes have important clinical applications in cell therapy of DMD partly via the targeted delivery of exosomal miR-29c
((Bier A, Berenstein P, Kronfeld N, Morgoulis D, Ziv-Av A, Goldstein H,
Kazimirsky G, Cazacu S, Meir R, Popovtzer R, Dori A, Brodie C. Placenta-derived
mesenchymal stromal cells and their exosomes exert therapeutic effects in
Duchenne muscular dystrophy. Biomaterials. 2018 May 3;174:67-78. doi:
10.1016/j.biomaterials.2018.04.055. [Epub ahead of print] PubMed PMID: 29783118.)).
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It is uncertain whether using cardiac [[drug]]s prophylactically in combinations for DMD is better than ACE-inhibitor alone. Our previous study showed no differences in left ventricular function between perindopril-bisoprolol and matched placebo after 36 months.

This study aimed to determine whether heart measures diverged after 60-month total follow-up. All participants had commenced open-label perindopril and bisoprolol when the original study ended. All consented to access to heart measures, undertaken as part of their clinical care. The primary outcome was the change in echo-measured ventricular ejection fraction from baseline according to original randomization.

Of the 75 participants reported originally, 65 (aged 16 ± 2.5 years) were re-recruited and had data for analysis. Adjusted primary outcomes included 44 participants (original arms: 'active' 21; 'placebo' 23), 48 for secondary outcomes, and 65 for 'headcount' analysis of those with ventricular dysfunction. Absolute LVEF% values reduced in both groups ('active': 62.5% ± 5.6% to 53.8% ± 4.0%; 'placebo': 60.6% ± 4.9% to 50.4% ± 8.5%). Despite trends favoring earlier introduction of therapy, change from baseline was similar between groups (adjusted mean difference: -7.7 (95% CI -16.4 to 1.0%)). However, more in the 'placebo' arm had died, had reduced LVEF%, and were taking additional heart medications.

While some patients may have benefited from 'early' (active) as opposed to 'delayed' (placebo) initiation of perindopril and bisoprolol, group-mean ventricular function did not differ between study arms after 60 months. Small numbers, absence of a control group, insensitivity of echo-ejection fraction, and additional drug use probably prevented divergence between groups
((Bourke JP, Bryant A, Landon G, Burn A, Spinty S, Quinlivan R, Alhaswani Z, Chadwick T, Muntoni F, Guglieri M; DMD Heart Study Group. Preventing Cardiomyopathy in Duchenne Muscular Dystrophy: Long-Term Follow-Up of Patients in the Randomised, Placebo-Controlled Drug-Trial of Perindopril and Bisoprolol. Eur J Neurol. 2025 Mar;32(3):e70097. doi: 10.1111/ene.70097. PMID: 40130400.))