Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25

Defective BVES-mediated feedback control of cAMP in muscular dystrophy

“…Consistent with our previous report 17 , our data showed that fasttwitch fibers (IIb and IIx) were more severely affected in BVES-KO muscles. Interestingly, the AMPK phosphorylation was dramatically increased in the fast fiber-dominant EDL muscles from BVES-KO mice, but not in the slow fiber-containing soleus muscles (see Supplementary Fig.…”

“…Genetic mutations in BVES were identified in patients with limb-girdle muscular dystrophy type R25 (LGMDR25) and cardiac arrhythmia 3,[8][9][10][11][12][13][14]12,15 . Similar muscle and heart dysfunction was reported in mice 16,17 , zebrafish 8 , Xenopus 18 and Drosophila 19 models with BVES deficiency, suggesting that BVES plays important, highly conserved functions in striated muscles.In this study, we employed genetic, pharmacological, biochemical and live cell imaging approaches to study the molecular pathogenesis of BVES-deficient muscular dystrophy. Our studies unveiled a role of BVES in providing a negative feedback control for ADCY9 to regulate the cAMP signaling in skeletal muscle.…”

“…Genetic mutations in BVES were identified in patients with limb-girdle muscular dystrophy type R25 (LGMDR25) and cardiac arrhythmia 3,[8][9][10][11][12][13][14]12,15 . Similar muscle and heart dysfunction was reported in mice 16,17 , zebrafish 8 , Xenopus 18 and Drosophila 19 models with BVES deficiency, suggesting that BVES plays important, highly conserved functions in striated muscles.…”

Systemic Delivery of Full-Length Dystrophin in DMD Mice

“…4a), which was signi cantly reduced in AAV-treated group (1060.0 ± 229.4, n = 13; p < 0.0001), suggesting that FL-dystrophin expression reduces muscle injury in dystrophic mice. To test if AAV-N1/M3/C6 treatment improves the muscle function, we measured the muscle contractility using an in vivo muscle test system 28,41,42 . The maximum plantar exion tetanic torque was measured during supramaximal electric stimulation of the tibial nerve at 150 Hz.…”

Paving the way for future gene therapies: A case study of scientific spillover from delandistrogene moxeparvovec

“…The MHCK7 promoter, comprising an α-myosin heavy chain (α-MHC) enhancer and a muscle creatine kinase (MCK) enhancer/promoter region, induces high transgene expression in skeletal and cardiac muscle. 75 It is therefore being used in the development of therapies for certain LGMD subtypes (including LGMD2B [dysferlinopathy], LGMD2C, LGMD2D, LGMD2E, and LGMDR25) 76 , 77 , 78 , 79 and may be useful for other muscular dystrophies. The promoter has also been shown to enable muscle-specific CRISPR-mediated gene editing in cultured cells and in mice.…”