Spatial mapping of CoQ10 repletion by BPM31510 in a genetic mouse model (Coq4) of coenzyme Q deficiency

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 because of 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 containing 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 Coq4^F147C mice, a novel genetic knock-in model of primary CoQ deficiency. Coenzyme Q9, the main form of CoQ in mice, and CoQ10 were significantly decreased in the brain, kidney, heart, and muscle of Coq4^F147C mice compared with Coq4^+/+ mice. BPM31510 treatment significantly increased oxidized CoQ10 levels across all tissues, mediated by the nanoliposome biodistribution of oxidized CoQ10 in BPM31510. MALDI-MS imaging demonstrated regional and spatial restoration of CoQ10 within the brain, including the cerebellum, myocardium, and renal cortex of Coq4^F147C 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 suborgan 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.