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

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 platf...

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Published in:	Molecular therapy. Methods & clinical development Vol. 25; pp. 264 - 277
Main Authors:	Fader, Kelly A., Pardo, Ingrid D., Kovi, Ramesh C., Somps, Christopher J., Wang, Helen Hong, Vaidya, Vishal S., Ramaiah, Shashi K., Sirivelu, Madhu P.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 09-06-2022 American Society of Gene & Cell Therapy Elsevier
Subjects:	adeno-associated virus (AAV) dorsal root ganglia (DRG) gene therapy neurobiomarker neurofilament light chain (NF-L) Original dorsal root ganglia (DRG) adeno-associated virus (AAV) gene therapy neurofilament light chain (NF-L) neurobiomarker
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Summary:	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 are needed to better characterize and manage the risk of DRG neurotoxicity in both nonclinical and clinical studies. Based on biological relevance, reagent availability, antibody cross-reactivity, DRG protein expression, and assay performance, neurofilament light chain (NF-L) emerged as a promising biomarker candidate. Dose- and time-dependent changes in NF-L were evaluated in male Wistar Han rats and cynomolgus monkeys following intravenous or intrathecal AAV injection, respectively. NF-L profiles were then compared against microscopic DRG lesions on day 29 post-dosing. In animals exhibiting DRG toxicity, plasma/serum NF-L was strongly associated with the severity of neuronal degeneration/necrosis and nerve fiber degeneration, with elevations beginning as early as day 8 in rats (≥5 × 1013 vg/kg) and day 14 in monkeys (≥3.3 × 1013 vg/dose). Consistent with the unique positioning of DRGs outside the blood-brain barrier, NF-L in cerebrospinal fluid was only weakly associated with DRG findings. In summary, circulating NF-L is a promising biomarker of AAV-induced DRG toxicity in nonclinical species. [Display omitted] Dorsal root ganglia (DRG) toxicity has been observed in preclinical studies with adeno-associated virus gene therapy. There is a critical need for biomarker development to better manage DRG toxicity risk in clinical trials. This manuscript demonstrates neurofilament light chain as a promising biomarker of DRG toxicity in rats and monkeys.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2329-0501 2329-0501
DOI:	10.1016/j.omtm.2022.03.017