Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primates
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) an...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050122001851 |
| _version_ | 1811177314774417408 |
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| author | Eric W. Johnson Jeffrey J. Sutherland Emily Meseck Cameron McElroy Deepa H. Chand Francis Fonyuy Tukov Eloise Hudry Kelley Penraat |
| author_facet | Eric W. Johnson Jeffrey J. Sutherland Emily Meseck Cameron McElroy Deepa H. Chand Francis Fonyuy Tukov Eloise Hudry Kelley Penraat |
| author_sort | Eric W. Johnson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T22:59:44Z |
| format | Article |
| id | doaj.art-ff357e0c44fd444d815f1c28922732c0 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-10T22:59:44Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-ff357e0c44fd444d815f1c28922732c02023-01-14T04:26:45ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-03-0128208219Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primatesEric W. Johnson0Jeffrey J. Sutherland1Emily Meseck2Cameron McElroy3Deepa H. Chand4Francis Fonyuy Tukov5Eloise Hudry6Kelley Penraat7Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USANovartis Institutes for BioMedical Research, Cambridge, MA 02139, USANovartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USANovartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USANovartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA; University of Illinois College of Medicine-Peoria, Children’s Hospital of Illinois, Peoria IL 61605, USANovartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USANovartis Institutes for BioMedical Research, Cambridge, MA 02139, USANovartis Institutes for BioMedical Research, Cambridge, MA 02139, USA; Corresponding author: Kelley Penraat, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.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.http://www.sciencedirect.com/science/article/pii/S2329050122001851adeno-associated virus 9 gene therapycerebrospinal fluiddorsal root ganglia/trigeminal ganglia pathologydorsal root ganglia toxicitynonclinical toxicologyneurofilament light chain |
| spellingShingle | Eric W. Johnson Jeffrey J. Sutherland Emily Meseck Cameron McElroy Deepa H. Chand Francis Fonyuy Tukov Eloise Hudry Kelley Penraat Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primates Molecular Therapy: Methods & Clinical Development adeno-associated virus 9 gene therapy cerebrospinal fluid dorsal root ganglia/trigeminal ganglia pathology dorsal root ganglia toxicity nonclinical toxicology neurofilament light chain |
| title | Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primates |
| title_full | Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primates |
| title_fullStr | Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primates |
| title_full_unstemmed | Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primates |
| title_short | Neurofilament light chain and dorsal root ganglia injury after adeno-associated virus 9 gene therapy in nonhuman primates |
| title_sort | neurofilament light chain and dorsal root ganglia injury after adeno associated virus 9 gene therapy in nonhuman primates |
| topic | adeno-associated virus 9 gene therapy cerebrospinal fluid dorsal root ganglia/trigeminal ganglia pathology dorsal root ganglia toxicity nonclinical toxicology neurofilament light chain |
| url | http://www.sciencedirect.com/science/article/pii/S2329050122001851 |
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