Primary Coenzyme Q10 (CoQ10) deficiency is a rare mitochondrial disorder caused by mutations in genes involved in CoQ biosynthesis (e.g., COQ4) that result in impaired mitochondrial respiration, oxidative stress, and dysfunction across multiple organ systems due to decreased mitochondrial levels of CoQ10. Although oral CoQ10 supplementation has been examined for standard of care, poor absorption and inadequate tissue and intracellular distribution have resulted in a lack of clinically significant efficacy. BPM31510 is a lipid nanoparticle formulation of oxidized CoQ10 designed to improve bioavailability and targeted uptake into the mitochondria. In the current study, we assessed the efficacy of BPM31510 to increase CoQ levels in Coq4F147C mice, a novel genetic knock-in model of primary CoQ deficiency. CoQ9, the main form of CoQ in mice, and CoQ10 were significantly decreased in brain, kidney, heart, and muscle of Coq4F147C mice compared to Coq4+/+ mice. BPM31510 treatment significantly increased oxidized CoQ10 levels across all tissues, mediated by the nanoliposome biodistribution of oxidized CoQ10 in BPM31510. MALDI-MSI demonstrated regional and spatial restoration of CoQ10 within the brain, including the cerebellum, myocardium, and renal cortex of Coq4F147C mice. These results demonstrate that BPM31510 successfully concentrates pharmacologically active CoQ10 in target tissues that are not reachable with oral therapy, in a genetic model of primary CoQ deficiency. We enabled the visualization of sub-organ CoQ10 localization to specifically demonstrate CoQ10 restoration. This study establishes proof-of-concept for spatial quinomics, a new methodology that combines spatial metabolomics with quinomics to evaluate next-generation CoQ10-based therapeutics for mitochondrial disorders.
Barriocanal-Casado et al. (Thu,) studied this question.