Circulating neurofilament light chain as a promising biomarker of AAV-induced dorsal root ganglia toxicity in nonclinical toxicology species

• DOI: 10.1016/j.omtm.2022.03.017
• Publication Date: 2022-03-29T00:59:32Z
• Authors: Kelly A. Fader; Ingrid D. Pardo; Ramesh C. Kovi; Christopher J. Somps; Helen Hong Wang; Vishal S. Vaidya; Shashi K. Ramaiah; Madhu P. Sirivelu
• Keywords: Neurotoxicity; Neurofilament; Infiltration (HVAC)

Adeno-associated virus (AAV)-induced dorsal root ganglia (DRG) toxicity has been observed in several nonclinical species, where lesions are characterized by neuronal degeneration/necrosis, nerve fiber degeneration, and mononuclear cell infiltration. As AAV vectors become an increasingly common platform for novel therapeutics, non-invasive biomarkers needed to better characterize manage the risk of DRG neurotoxicity both clinical studies. Based on biological relevance, reagent availability, antibody cross-reactivity, protein expression, assay performance, neurofilament light chain (NF-L) emerged as a promising biomarker candidate. Dose- time-dependent changes NF-L were evaluated male Wistar Han rats cynomolgus monkeys following intravenous or intrathecal injection, respectively. profiles then compared against microscopic day 29 post-dosing. In animals exhibiting toxicity, plasma/serum was strongly associated with severity degeneration/necrosis elevations beginning early 8 (≥5 × 1013 vg/kg) 14 (≥3.3 vg/dose). Consistent unique positioning DRGs outside blood-brain barrier, cerebrospinal fluid only weakly findings. summary, circulating is AAV-induced species.