Converging lines of evidence implicate dysregulated neuronal energy metabolism as a driver of neuronal death in many neurodegenerative diseases, including Parkinson’s Disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of clean-surfaced, catalytically active gold nanocrystals shown to enhance neuronal metabolic energy, reduce oxidative stress, and improve protein homeostasis. CNM-Au8 catalyzes the oxidation of nicotinamide adenine dinucleotide (NADH), an energetic metabolite essential for ATP production, as well as catalyzing the reduction of oxygen radicals.
Seven Tesla 31-phosphorous magnetic resonance spectroscopy (31P-MRS) was used to detect levels of energy metabolites including NAD+, NADH, ATP (alpha-, beta-, and gamma-ATP), and mono- and diester phospholipids in the brains of 13 PD participants and 11 MS participants at baseline and following 12-weeks of treatment with CNM-Au8. Whole brain spectra were collected in ~600 voxels at a spatial resolution of 2 cm3 with a full volume coil. A partial volume coil was used to determine the NAD+/NADH ratio by imaging the parietal and occipital lobes bilaterally as a single voxel.
CNM-Au8 treatment resulted in improved brain NAD+/NADH ratio (primary endpoint, paired t-test, p=0.0371), driven by an increase in NAD+ and a decrease in NADH (secondary endpoint, paired t-test, p=0.0264). CNM-Au8 treatment resulted in homeostatic effects on brain bioenergetic phosphorous metabolites including ATP, where study participants with ATP levels less than the baseline mean significantly increased whole-brain ATP levels, while patients with baseline levels greater than the baseline mean decreased levels to the population mean (r2 = 0.711, p<0.0001).
Results from the REPAIR clinical trials demonstrate CNS target engagement with CNM-Au8. These data provide clinical evidence of the effect of CNM-Au8 treatment on brain energetic metabolism and support its candidacy as a disease-modifying therapy for the treatment of neurodegenerative diseases associated with dysregulated neuronal energy metabolism.