Abstract:

Patients with GNE myopathy, a progressive and debilitating disease caused by a genetic defect in sialic acid biosynthesis, rely on supportive care and eventually become wheelchair-bound. To elucidate whether GNE myopathy is treatable at a progressive stage of the disease, we examined the efficacy of sialic acid supplementation on symptomatic old GNE myopathy mice that have ongoing, active muscle degeneration. We examined the therapeutic effect of a less metabolized sialic acid compound (6'-sialyllactose) or free sialic acid (N-acetylneuraminic acid) by oral, continuous administration to 50-week-old GNE myopathy mice for 30 weeks. To evaluate effects on their motor performance in living mice, spontaneous locomotion activity on a running wheel was measured chronologically at 50, 65, 72 and 80 weeks of age. The size, force production, and pathology of isolated gastrocnemius muscle were analysed at the end point. Sialic acid level in skeletal muscle was also measured. Spontaneous locomotion activity was recovered in 6'-sialyllactose-treated mice, while NeuAc-treated mice slowed the disease progression. Treatment with 6'-sialyllactose led to marked restoration of hyposialylation in muscle and consequently to robust improvement in the muscle size, contractile parameters, and pathology as compared to NeuAc. This is due to the fact that 6'-sialyllactose is longer working as it is further metabolized to free sialic acid after initial absorption. 6'-sialyllactose ameliorated muscle atrophy and degeneration in symptomatic GNE myopathy mice. Our results provide evidence that GNE myopathy can be treated even at a progressive stage and 6'-sialyllactose has more remarkable advantage than free sialic acid, providing a conceptual proof for clinical use in patients.

日本語要旨:

縁取り空胞を伴う遠位型ミオパチー(DMRV)は、シアル酸生合成経路の律速酵素の遺伝的欠陥によって発症する慢性進行性の遺伝性筋疾患である。本症の発症にはシアル酸の低下が重要である。今回、ミオパチーを発症した50週齢の高齢DMRVマウスに対して、N-acetylneuraminic acid (NeuAc)またはシアリル乳糖(6’-SL)を30週間継続投与する試験を行い，表現型により治療効果を判定するとともに，投与化合物の効果の差異や特徴を明らかにした。自発運動量を50、65、72、80週齢で経時的に計測し、試験終了時に腓腹筋のサイズ、収縮力、筋病理と各組織シアル酸レベルを解析した。6’-SL投与によってマウスの自発運動量は経時的に回復した。6’-SLは骨格筋シアル酸レベルを著明に回復させ、腓腹筋サイズ、収縮力、筋病理を改善した。NeuAcの治療効果は6’-SLに及ばなかった。6’-SLはNeuAcに比し体内を留まる時間が長く、吸収された後それ自体として働くとともに、体内を循環している間にNeuAcへと代謝されさらに働くと考えられた。6’-SLのような化合物がもつ特性は、DMRV患者の実際の治療薬開発へ応用されるべきものである。