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Chronic activation of NF-κB is a key driver of muscle degeneration and suppression of muscle regeneration in Duchenne muscular dystrophy. Edasalonexent (CAT-1004) is an orally-administered novel small molecule that covalently links two bioactive compounds (salicylic acid and docosahexaenoic acid) that inhibit NF-κB. This placebo-controlled, proof-of-concept phase 2 study with open-label extension in boys ≥4-8 years old with any dystrophin mutation examined the effect of edasalonexent (67 or 100 mg/kg/day) compared to placebo or off-treatment control. Endpoints were safety/tolerability, change from baseline in MRI T

The purpose of this study was to evaluate skeletal muscle composition of lower extremity muscles in a manifesting female carrier of Duchenne muscular dystrophy (MFC DMD ) using magnetic resonance imaging (MRI) and spectroscopy (MRS). MRI/MRS was performed on the lower extremities and heart of a MFC DMD (47years, 51kg) on four occasions within 21months and in a control subject. Heterogeneity and asymmetry among muscles in the MFC DMD was observed in lipid fraction and mean transverse relaxation time (T 2 ) of lower extremity muscles with some muscles presenting as unaffected (e.g., rectus femoris) and others showing substantial deterioration and lipid infiltration (e.g., vasti muscles). There was an association of abnormal MRI findings and strength and motor function. Over the 21months a small decrease in CSA max and increase in lipid fraction and T 2 was observed in the MFC DMD in some muscles. In summary, this MFC DMD revealed significant imaging evidence of pathologic heterogeneity among muscles. Furthermore, this study shows the feasibility of combining various quantitative MRI and MRS approaches to monitor skeletal muscle involvement.

Boys with Duchenne muscular dystrophy (DMD) have an increased incidence of fracture and low bone mineral density (BMD). Previous studies of bone in DMD have utilized dual-emission X-ray absorptiometry (DXA); however, this technique yields monoplanar bone density. Magnetic resonance imaging (MRI) techniques on the other hand provide 3-dimensional structural information regarding bone structure and composition. Subjects for this cross-sectional analysis were drawn from the milticenter ImagingDMD study and included 14 boys with DMD (age 7–11 years, mean 9.3 ± 1.6 years) and 7 control subjects (age 7–11 years, mean 9.4 ± 1.5 years). MRI T1-weighted images taken at the mid-tibia were used to determine the following bone volumetric measures: overall bone cross-sectional area (CSA), cortical bone cross-sectional area (cCSA) and trabecular bone cross-sectional area (tCSA). Mid-tibia trabecular bone composition was assessed using the same T1-weighted cross-sectional image with and without fat suppression to determine average trabecular bone fat signal intensity. Boys with DMD had lower mean tibial CSA compared to controls (p = 0.001), lower mean cCSA (p = 0.0005) and lower mean tCSA (p = .03). The mean tibial trabecular fat content was not significantly different between the two groups (p = 0.38). This study demonstrates that boys with DMD have significant differences in measures of bone cross-sectional area, affecting both the cortical and trabecular bone, with the reduction in cortical bone being the most marked (∼30% reduced). There is a clear need to better characterize the abnormalities in bone of boys with DMD in order to improve both direct medical management of osteoporoesis in this population as well as inform the development of clinical trials to address this issue.

Magnetic resonance imaging (MRI) and spectroscopy (MRS) show promise as unbiased non-invasive measures of disease progression in neuromuscular diseases. The ImagingDMD study is a longitudinal study that aims to validate the use of MRI and MRS at multiple sites in a large cohort of boys with Duchenne muscular dystrophy (DMD). To date, 121 boys with DMD, aged 5–14 years, and 24 unaffected boys have completed baseline measures for this study. All boys could walk and climb stairs at the time of enrollment. The boys completed an MR exam that included MRI measures of muscle transverse relaxation time (MRI T2) and MRS measures of muscle composition (lipid: (lipid + water)) and the T2 of the water component of muscle (MRS T2). MRS T2 and MRI T2 are elevated by muscle damage, edema, and inflammation, and MRI T2 is also affected by intramuscular fat. Boys with DMD had greater MRI T2 (soleus (Sol): DMD 42.9 ± 5.4 ms, Con 33.6 ± 1.6 ms, vastus lateralis (VL): DMD 49.0 ± 9.8 ms, Con 34.2 ± 2.2 ms), MRS T2 (Sol: DMD 31.7 ± 2.3 ms, Con 28.2 ± 0.6 ms, VL: DMD 31.6 ± 2.4 ms, 29.0 ± 0.8 ms), and lipid: (lipid + water) (Sol: DMD 0.37 ± 0.16, Con 0.22 ± 0.08, VL: DMD 0.48 ± 0.25, Con 0.20 ± 0.07) than unaffected boys (p

Pompe disease is a rare, progressive and often fatal neuromuscular disorder resulting from mutations in the gene for acid alpha-glucosidase (GAA), an enzyme necessary to degrade glycogen. The deficiency or dysfunction of the GAA enzyme leads to lysosomal glycogen accumulation in multiple tissues and results in cardiac and skeletal muscle dysfunction. Glycogen content may vary between muscle groups and in regions of the same muscle. Most importantly, glycogen content may change during the course of the disease. Enzyme replacement therapy (ERT) is the only FDA approved treatment for Pompe disease. However, translation from preclinical to clinical studies is challenged by the lack of reliable, noninvasive outcome measures suitable for repeated evaluations. Effect of treatment is commonly measured by muscle glycogen clearance using biochemical assays, which rely on muscle biopsy. In this study, we used Magnetic Resonance Imaging (MRI) of the thigh and lower leg muscles to evaluate the effect of 12 and 24 weeks of ERT in individuals affected by Late Onset Pompe Disease (LOPD) (n = 4; age 35–50). Maximum cross-sectional area (CSAmax) – an index of muscle mass – increased in average by 1.16- and 1.09-fold at 12 weeks, and by 1.13- and 1.09-fold at 24 weeks in the lower and upper legs respectively. In addition, we studied the MR proton traverse relaxation time (T2) – an index of muscle damage and edema – by applying a mono exponential decay equation to four echo times (TE). At 24 weeks, T2 values reduced by 1.20- and 1.10-fold in the lower and upper legs, respectively. These data demonstrate an increase in CSAmax associated accompanied by a reduction of T2 value, which may suggest a reduction of glycogen accumulation and an increase of contractile myofibers. In support of this hypothesis, biochemical assay from muscle biopsy specimens showed a reduction of glycogen concentration by 2.21-fold at week 24 compare to baseline.