MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates

Gene Ther. 2018 Apr;25(2):104-114. doi: 10.1038/s41434-018-0010-2. Epub 2018 Mar 13.

Abstract

Brain-derived neurotrophic factor (BDNF) gene delivery to the entorhinal cortex is a candidate for treatment of Alzheimer's disease (AD) to reduce neurodegeneration that is associated with memory loss. Accurate targeting of the entorhinal cortex in AD is complex due to the deep and atrophic state of this brain region. Using MRI-guided methods with convection-enhanced delivery, we were able to accurately and consistently target AAV2-BDNF delivery to the entorhinal cortex of non-human primates; 86 ± 3% of transduced cells in the targeted regions co-localized with the neuronal marker NeuN. The volume of AAV2-BDNF (3 × 108 vg/µl) infusion linearly correlated with the number of BDNF labeled cells and the volume (mm3) of BDNF immunoreactivity in the entorhinal cortex. BDNF is normally trafficked to the hippocampus from the entorhinal cortex; in these experiments, we also found that BDNF immunoreactivity was elevated in the hippocampus following therapeutic BDNF vector delivery to the entorhinal cortex, achieving growth factor distribution through key memory circuits. These findings indicate that MRI-guided infusion of AAV2-BDNF to the entorhinal cortex of the non-human primate results in safe and accurate targeting and distribution of BDNF to both the entorhinal cortex and the hippocampus. These methods are adaptable to human clinical trials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / administration & dosage*
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Contrast Media / pharmacokinetics
  • Dependovirus / genetics*
  • Entorhinal Cortex / metabolism*
  • Female
  • Gadolinium / pharmacokinetics
  • Genetic Vectors
  • Green Fluorescent Proteins / metabolism
  • Heterocyclic Compounds / pharmacokinetics
  • Hippocampus / metabolism
  • Macaca fascicularis
  • Macaca mulatta
  • Magnetic Resonance Imaging / methods*
  • Male
  • Neurons / virology
  • Organometallic Compounds / pharmacokinetics
  • Protein Transport

Substances

  • Brain-Derived Neurotrophic Factor
  • Contrast Media
  • Heterocyclic Compounds
  • Organometallic Compounds
  • gadoteridol
  • Green Fluorescent Proteins
  • Gadolinium