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Neurofilament Light Chain and Dorsal Root Ganglia Injury After Adeno-Associated Virus 9 Gene Therapy in Nonhuman Primates

Johnson, Eric, Sutherland, Jeffrey, Meseck, Emily, McElroy, Cameron, Chand, Deepa, Tukov, Francis, Hudry, Eloise and Penraat, Kelley (2023) Neurofilament Light Chain and Dorsal Root Ganglia Injury After Adeno-Associated Virus 9 Gene Therapy in Nonhuman Primates. Molecular therapy: Methods and Clinical Development, 28. pp. 208-219. ISSN 2329-0501


In nonhuman primates (NHPs), adeno-associated virus serotype 9 (AAV9) vectorized gene therapy can cause asymptomatic microscopic injury to dorsal root (DRG) and trigeminal ganglia (TG) somatosensory neurons, causing neurofilament light chain (NfL) to diffuse into cerebrospinal fluid (CSF) and blood. Data from 260 cynomolgus macaques administered vehicle or AAV9 vectors (intrathecally or intravenously) were analyzed to investigate NfL as a soluble biomarker for monitoring DRG/TG microscopic findings. The incidence of key DRG/TG findings with AAV9 vectors was 78% (maximum histopathology severity, moderate) at 2–12 weeks post-dose. When examined up to 52 weeks post-dose, the incidence was 42% (maximum severity, minimal). Terminal NfL concentrations in plasma, serum, and CSF correlated with microscopic severity. After 52 weeks, NfL returned to pre-dose baseline concentrations, correlating with microscopic findings of lesser incidence and/or severity compared with interim time points. Blood and CSF NfL concentrations correlated with asymptomatic DRG/TG injury, suggesting that monitoring serum and plasma concentrations is as useful for assessment as more invasive CSF sampling. Longitudinal assessment of NfL concentrations related to microscopic findings associated with AAV9 administration in NHPs indicates NfL could be a useful biomarker in nonclinical toxicity testing. Caution should be applied for any translation to humans.

Item Type: Article
Keywords: Adeno-associated virus 9 gene therapy; cerebrospinal fluid; dorsal root ganglia/trigeminal ganglia pathology; dorsal root ganglia toxicity; nonclinical toxicology; neurofilament light chain; nonhuman primates; peripheral neuropathy; sensory neuropathy; soluble biomarkers.
Date Deposited: 31 Jan 2023 00:45
Last Modified: 31 Jan 2023 00:45


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