Brain Targeting and Toxicological Assessment of the Extracellular Vesicle-Packaged Antioxidant Catalase-SKL Following Intranasal Administration in Mice.

Sarah H Hayes, Qingfan Liu, Sureka Selvakumaran, Matthew J Haney, Elena V Batrakova, Brian L Allman, Paul A Walton, Patti Kiser, Shawn N Whitehead

Neurotoxicity research 2021 Oct

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The antioxidant enzyme catalase represents an important therapeutic target due to its role in mitigating cellular reactive oxygen species that contribute to the pathogenesis of many disease states. Catalase-SKL (CAT-SKL), a genetically engineered, peroxisome-targeted, catalase derivative, was developed in order to increase the therapeutic potential of the enzyme, and has previously been shown to be effective in combating oxidative stress in a variety of in vitro and in vivo models, thereby mitigating cellular degeneration and death. In the present study we addressed important considerations for the development of an extracellular vesicle-packaged version of CAT-SKL (evCAT-SKL) as a therapeutic for neurodegenerative diseases by investigating its delivery potential to the brain when administered intranasally, and safety by assessing off-target toxicity in a mouse model. Mice received weekly intranasal administrations of evCAT-SKL or empty extracellular vesicles for 4 weeks. Fluorescent labeling for CAT-SKL was observed throughout all sections of the brain in evCAT-SKL-treated mice, but not in empty extracellular vesicle-treated mice. Furthermore, we found no evidence of gross or histological abnormalities following evCAT-SKL or empty extracellular vesicle treatment in a full-body toxicological analysis. Combined, the successful brain targeting and the lack of off-target toxicity demonstrates that intranasal delivery of extracellular vesicle-packaged CAT-SKL holds promise as a therapeutic for addressing neurological disorders. © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Citation

Sarah H Hayes, Qingfan Liu, Sureka Selvakumaran, Matthew J Haney, Elena V Batrakova, Brian L Allman, Paul A Walton, Patti Kiser, Shawn N Whitehead. Brain Targeting and Toxicological Assessment of the Extracellular Vesicle-Packaged Antioxidant Catalase-SKL Following Intranasal Administration in Mice. Neurotoxicity research. 2021 Oct;39(5):1418-1429