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

Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primates

“…Biomarkers commonly used for neurodegenerative investigations include NfL, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase, Tau, and neurofilament heavy chain (NfH). 1 , 14 , 16 In several early nonclinical studies (not published), neopterin, ubiquitin C-terminal hydrolase, Tau, GFAP, and NfL were assessed, and NfL results were the most consistent and sensitive in our laboratory. Therefore, we focused our investigative efforts on NfL, a subunit of neurofilament and one of several cytoskeletal intermediate filaments (approximately 10 nm in diameter) that provides structural support, regulates axonal diameter, and is present in all neurons, including the DRG of humans and animals.…”

“…Spinal sensory or dorsal root ganglia (DRG) and trigeminal ganglia (TG) microscopic findings, often referred to collectively as DRG toxicity, have emerged in association with adeno-associated virus (AAV) gene therapies administered systemically or to the cerebrospinal fluid (CSF) in nonclinical studies involving nonhuman primates (NHPs), rats, and mini-pigs. 1 , 2 , 3 , 4 The described microscopic findings are heterogeneously distributed across multiple DRG and/or TG within each animal. In most cases, such microscopic lesions remain clinically silent or asymptomatic in NHPs, outside the limits of detection of such sensory changes in this laboratory species in a nonclinical toxicology study setting, and potential translation to patients is uncertain.…”

“…In mini-pigs, clinical proprioceptive deficits have been observed in life that were associated with microscopic findings, 2 whereas clinical observations were reportedly rarely observed in rats, similar to NHPs. 1 As such, identifying and characterizing relevant soluble biomarkers as surrogates for monitoring AAV serotype 9 (AAV9)–related microscopic neuropathologic changes of the sensory ganglia would be valuable in nonclinical and clinical settings, albeit with different considerations and caveats in each of those settings.…”

Circulating neurofilaments to track dorsal root ganglion toxicity risks with AAV-mediated gene therapy

“…identify plasma Nf-L as a potential non-invasive biomarker to monitor the development of DRG toxicity after AAV-mediated gene therapy. 1 …”

“…used a targeted approach to select Nf-L and ubiquitin C-terminal hydrolase (UCH-L1) as candidate biomarkers, based on commercial reagent availability, antibody cross reactivity, assay performance, and DRG protein expression. 1 Dose- and time-dependent changes were evaluated after AAV gene therapy, comparing protein profiles with DRG pathology. Serum/plasma Nf-L levels were strongly associated with the severity of neuronal degeneration and axonal loss, with elevations commencing from day 8 in rodents and day 14 in monkeys.…”