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Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by muscle dystrophin deficiency. Disease mechanisms caused by primary dystrophin deficiency are not well elucidated. Recently, urinary 11,15-dioxo-9α-hydroxy-, 2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor PGDM) was shown to be a major metabolite of prostaglandin D2 (PGD2) and reflects to its biosynthesis. Here, the hypothesis that PGD2-mediated inflammation is involved in the pathology of DMD was examined by measuring tetranor PGDM in urine of DMD patients. We measured tetranor PGDM in the patients’ urine samples using LC–MS/MS. One hundred seventeen genetically confirmed DMD patients from 4 to 15years of age were enrolled in this study and their first morning urines were obtained at 191 points. Age matched 71 male controls were recruited from healthy relatives or volunteers and first morning urines were obtained at 79 points. The urinary tetranor PGDM levels were 3.08±0.15 and 6.90±0.35ng/mg creatinine (mean ±SE) in 79 control and 191 DMD points, respectively. The mean level in the DMD points was approximately 2.2-times higher than in the control points (p <0.05). Especially, urinary tetranor PGDM level increases with age of DMD patients. It stayed nearly 1.5 times higher than control until 7years old but surged at the age of 8 to a significantly higher level. On the other hand, the level in controls does not show no significant difference between ages. Urinary tetranor PGDM levels were elevated in DMD patients and became higher with advancing age. It was suggested that PGD2-mediated inflammation should be taken into consideration in understanding the pathology of DMD, especially in older patients. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. Antisense oligonucleotide (AO)-mediated exon skipping therapy has been proposed for the treatment of DMD, producing in-frame mRNA from the out-of-frame mRNA by inducing exon shipping. Generally, the 6-min walk test has been used for evaluating the response to newly developed therapies, whereas it is difficult to measure the fine change. In this study three-dimensional gait analysis was used for measuring the therapeutic effect of AO85, which is an 18-mer antisense RNA/2-O, 4-C ethylene-bridged nucleic acid (ENA) chimera inducing the exon 45 skipping, in DMD case. An 8-year-old DMD case with exon 44 deletion was enrolled and received a 0.5mg/kg IV infusion of AO85, which was administered at 1-week interval for 4weeks. In addition to the conventional tests, his kinematic and kinetic data were collected with a 10-camera MAC3D motion analysis system (Motion Analysis Corp., Santa Rosa, CA) synchronized with an embedded Kistler force plate (Kistler Instruments Corp., Amherst, NY). This system monitors the three dimensional coordinates of the markers which were placed over the anatomical landmarks. The gait parameters were extracted using nMotion musculous (nac Image Technology Inc, Tokyo, Japan). The walking distances for 6min before and after treatment were not apparently changed (360m and 385m, respectively). On the other hand, three-dimensional gait analysis revealed the decreased joint torques at knee and ankle. Furthermore, the motion of his center of mass in the vertical direction during gait was reduced. These results indicate that the treatment with AO85 improved his walking motion. Three-dimensional gait analysis could find the fine change of motor function that was not able to be detected by the conventional 6-min walk test, and is the promising method to evaluate the efficacy of exon skipping therapy. [Copyright &y& Elsevier]