P.11.16 Three-dimensional gait analysis of Duchenne muscular dystrophy: A trial to evaluate the therapeutic effect of RNA/ENA chimera antisense oligonucleotide that induces dystrophin exon 45 skipping

Abstract

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 0.5 mg/kg IV infusion of AO85, which was administered at 1-week interval for 4 weeks. 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 6 min before and after treatment were not apparently changed (360 m and 385 m, 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.