Friedreich’s Ataxia (FA) is a devastating genetic disease caused by a trinucleotide repeat expansion that diminishes expression of the frataxin (FXN) protein. Low FXN expression levels cause progressive deficits in cellular respiration and cell death, with pronounced impact to non-regenerative cell types (neurons, cardiomyocytes). There are no current treatments that directly address FXN deficiency. Leveraging our high throughput directed evolution AAV engineering platform, Capsida has identified a systemically administered (IV) capsid that achieves NHP brain-wide biodistribution transducing large percentages of neurons in FA-related brain areas, as well as delivering cardiac and sensory tissue transduction. In an NHP study dosing a small pool of capsids simultaneously (N=3 NHP), the engineered capsid drives RNA expression levels ~100x higher than AAV9 in the central nervous system (CNS), while maintaining similar RNA expression in cardiac tissue, and ~10x de-targeting of liver. When the drug candidate, CAP-004, was administered IV as a single variant at a low to moderate dose (N=3 NHP), the engineered capsid delivering human FXN transduced more than 80% of cerebellar Purkinje cells, dentate nucleus neurons, motor neurons in the cortex and spinal cord, and nearly 30% of cardiac tissue area. FXN protein levels in treated NHPs were 8.2x higher than endogenous levels in the motor cortex and 1.7x in the heart as measured by ELISA. Moreover, substantial FXN RNA expression was detected in the retina (~1E6 copies/ug RNA) suggesting potential benefit for sensory vision loss experienced by FA patients. Significant de-targeting of the liver and other non-target tissues contributed to the favorable safety profile characterized by no adverse immunogenicity, clinical pathology, and histopathology findings. Thus, CAP-004 produces therapeutically meaningful FXN expression in CNS, cardiac, and sensory regions impacted by disease and has the potential to become a best-in-class therapy for FA. Data in this abstract were presented in poster form at the 2024 International Congress for Ataxia Research.