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 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.