Parkinson病の病態解明と次世代創薬

抄録

The landscape of Parkinson disease (PD) treatment is shifting globally from symptomatic management to disease–modifying therapies (DMTs) ; however, clinical trials targeting α–synuclein aggregation or neuroinflammation have yet to yield definitive success. In this context, researchers at Fujita Health University have identified the breakdown of ATP homeostasis as a core pathological mechanism. Large–scale registry analyses revealed a distinct metabolic shift in PD patients characterized by reduced glycolysis and compensatory upregulation of fatty acid β–oxidation. Specifically, dysfunction was identified in the ATP salvage pathway, marked by a systemic depletion of hypoxanthine, a key precursor for ATP resynthesis. To address this, a novel ATP augmentation therapy was developed combining inosine, a hypoxanthine precursor, with febuxostat, a xanthine oxidoreductase (XOR) inhibitor. This drug repositioning strategy aims to restore brain ATP levels and provide mitochondrial protection by efficiently supplying hypoxanthine and preventing its degradation. Validated in animal models, this innovative approach is currently undergoing investigator–initiated clinical trials to verify its efficacy in suppressing disease progression.