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

Eric W Johnson; Jeffrey J Sutherland; Emily Meseck; Cameron McElroy; Deepa H Chand; Francis Fonyuy Tukov; Eloise Hudry; Kelley Penraat

doi:10.1016/j.omtm.2022.12.012

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

Mol Ther Methods Clin Dev. 2022 Dec 26:28:208-219. doi: 10.1016/j.omtm.2022.12.012. eCollection 2023 Mar 9.

Authors

Eric W Johnson¹, Jeffrey J Sutherland¹, Emily Meseck², Cameron McElroy², Deepa H Chand^{2

3}, Francis Fonyuy Tukov², Eloise Hudry¹, Kelley Penraat¹

Affiliations

¹ Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
² Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
³ University of Illinois College of Medicine-Peoria, Children's Hospital of Illinois, Peoria IL 61605, USA.

Abstract

In nonhuman primates (NHPs), adeno-associated virus serotype 9 (AAV9) vectorized gene therapy can cause asymptomatic microscopic injury to dorsal root ganglia (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 after the dose. When examined up to 52 weeks after the dose, the incidence was 42% (maximum histopathology 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.

Keywords: adeno-associated virus 9 gene therapy; cerebrospinal fluid; dorsal root ganglia toxicity; dorsal root ganglia/trigeminal ganglia pathology; neurofilament light chain; nonclinical toxicology; nonhuman primates; peripheral neuropathy; sensory neuropathy; soluble biomarkers.