多系統萎縮症の病態抑止治療update

抄録

Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by autonomic dysfunction, cerebellar ataxia, and parkinsonism. It is classified into two subtypes : cerebellar (MSA–C) and parkinsonian (MSA–P). The median survival time from onset is approximately nine years. Despite extensive research efforts, no effective disease–modifying therapies have been established to date. However, recent advances in genetic studies have shed light on potential therapeutic strategies. Pathologically, MSA is classified as an α–synucleinopathy due to the presence of glial cytoplasmic inclusions primarily composed of aggregated α–synuclein. Therapeutic approaches targeting α–synuclein include inhibiting its propagation, suppressing its gene expression, enhancing its degradation, and preventing its aggregation. Genetic research has identified susceptibility loci such as PLA2G4C and COQ2, which are implicated in MSA pathogenesis. Notably, COQ2 variants disrupt coenzyme Q10 (CoQ10) biosynthesis, highlighting its potential role in disease progression. We have developed ubiquinol, the reduced form of CoQ10 with superior bioavailability, as a promising therapeutic candidate. Following preclinical safety studies and a successful Phase 1 clinical trial, a Phase 2 multicenter, placebo–controlled, double–blind trial was launched in 2018. This trial involved 139 patients who received 48 weeks of treatment with ubiquinol or placebo. The primary endpoint, the UMSARS Part 2 score, showed a significant slowing of disease progression in the ubiquinol group (p = 0.023). Safety analysis confirmed its tolerability. In recent years, disease–modifying therapies have seen rapid development for monogenic disorders. However, progress in the treatment of more prevalent sporadic neurodegenerative diseases has been slower. Incremental advancements, such as those described here, bring hope that in the near future, multiple therapeutic options will enable early detection and effective suppression of neurodegenerative disease progression.