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Safety Assessment of AAV2-hGDNF Administered via Intra-Cerebral Injection in Rats for treatment of Parkinson’s Disease.

  • Terse, Pramod S.1
  • Kells, Adrian P.2
  • Noker, Patricia3
  • Wright, J Fraser4
  • Bankiewicz, Krystof S.2, 5
  • 1 National Center for Advancing Translational Sciences, NIH, Rockville, MD, USA
  • 2 Brain Neurotherapy Bio, OH, USA
  • 3 Southern Research Institute, Birmingham, AL, USA
  • 4 Center for Definitive and Curative Medicine, Stanford University School of Medicine, CA, USA
  • 5 The Ohio State University, Columbus, OH, USA.
Published Article
International journal of toxicology
Publication Date
Nov 02, 2020
DOI: 10.1177/1091581820966315
PMID: 33131343
PMCID: PMC8171122
PubMed Central
  • Article


Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotective biologic in Parkinson’s disease models. AAV2-hGDNF safety was assessed in rats treated with a single intracerebral dose of vehicle, 6.8×108, 6.8×109, or 5.2×1010 vector genomes (vg)/dose followed by interim sacrifices on Day 7, 31, 90, and 376. There were no treatment related effects observed on food consumption, body weight, hematology, clinical chemistry, coagulation parameters, neurobehavioral parameters, organ weights or serum GDNF and anti-GDNF antibody levels. Increased serum anti-AAV2 neutralizing antibody titers were observed in the 5.2 × 1010 vg/dose group. Histopathological lesions were observed at the injection site in the 6.8 × 109 vg/dose (Day 7) and 5.2 × 1010 vg/dose groups (Days 7 and 31) and consisted of gliosis, mononuclear perivascular cuffing, intranuclear inclusion bodies, and/or apoptosis on Day 7 and mononuclear perivascular cuffing on Day 31. GDNF immunostaining was observed in the injection site in all dose groups through Day 376 indicating no detectable impacts of anti-AAV2 neutralizing antibody. There was no evidence of increased expression of Calcitonin Gene-Related Peptide or Swann cell hyperplasia in the cervical and lumbar spinal cord or medulla oblongata at the 5.2 × 1010 vg/dose level indicating lack of hyperplastic effects. In conclusion, no systemic toxicity was observed and the local toxicity observed at the injection site appeared to be reversible demonstrating a promising safety profile of intracerebral AAV2-GDNF delivery. Furthermore, an intracerebral dose of 6.8 × 108 AAV2-GDNF vg/dose was considered to be a no observed adverse effect level in rat.

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