PMID- 36700120
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230202
IS  - 2329-0501 (Print)
IS  - 2329-0501 (Electronic)
IS  - 2329-0501 (Linking)
VI  - 28
DP  - 2023 Mar 9
TI  - Neurofilament light chain and dorsal root ganglia injury after adeno-associated 
      virus 9 gene therapy in nonhuman primates.
PG  - 208-219
LID - 10.1016/j.omtm.2022.12.012 [doi]
AB  - 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.
CI  - (c) 2022 The Authors.
FAU - Johnson, Eric W
AU  - Johnson EW
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
FAU - Sutherland, Jeffrey J
AU  - Sutherland JJ
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
FAU - Meseck, Emily
AU  - Meseck E
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
FAU - McElroy, Cameron
AU  - McElroy C
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
FAU - Chand, Deepa H
AU  - Chand DH
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
AD  - University of Illinois College of Medicine-Peoria, Children's Hospital of 
      Illinois, Peoria IL 61605, USA.
FAU - Tukov, Francis Fonyuy
AU  - Tukov FF
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
FAU - Hudry, Eloise
AU  - Hudry E
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
FAU - Penraat, Kelley
AU  - Penraat K
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
LA  - eng
PT  - Journal Article
DEP - 20221226
PL  - United States
TA  - Mol Ther Methods Clin Dev
JT  - Molecular therapy. Methods & clinical development
JID - 101624857
PMC - PMC9852542
OTO - NOTNLM
OT  - adeno-associated virus 9 gene therapy
OT  - cerebrospinal fluid
OT  - dorsal root ganglia toxicity
OT  - dorsal root ganglia/trigeminal ganglia pathology
OT  - neurofilament light chain
OT  - nonclinical toxicology
OT  - nonhuman primates
OT  - peripheral neuropathy
OT  - sensory neuropathy
OT  - soluble biomarkers
COIS- E.M., C.M., D.H.C., and F.F.T. are employees of Novartis Pharmaceuticals 
      Corporation, East Hanover, NJ. E.W.J., J.J.S., E.H., and K.P. are employees of 
      Novartis Institutes for BioMedical Research, Cambridge, MA. All authors own 
      Novartis stock or other equities.
EDAT- 2023/01/27 06:00
MHDA- 2023/01/27 06:01
PMCR- 2022/12/26
CRDT- 2023/01/26 02:53
PHST- 2022/09/19 00:00 [received]
PHST- 2022/12/22 00:00 [accepted]
PHST- 2023/01/26 02:53 [entrez]
PHST- 2023/01/27 06:00 [pubmed]
PHST- 2023/01/27 06:01 [medline]
PHST- 2022/12/26 00:00 [pmc-release]
AID - S2329-0501(22)00185-1 [pii]
AID - 10.1016/j.omtm.2022.12.012 [doi]
PST - epublish
SO  - Mol Ther Methods Clin Dev. 2022 Dec 26;28:208-219. doi: 
      10.1016/j.omtm.2022.12.012. eCollection 2023 Mar 9.