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Updated: Mar 24, 2026
Subpial Adeno-associated Virus 9 AAV9 Vector Delivery in Adult Mice
Published on: July 13, 2017
Axonal transport of AAV9 in nonhuman primate brain
F Green1, L Samaranch1, H S Zhang2
1Department of Neurological Surgery, University of California-San Francisco, San Francisco, CA, USA.
Abstract:
A pilot study in nonhuman primates was conducted, in which two Rhesus macaques received bilateral parenchymal infusions of adeno-associated virus serotype 9 encoding green fluorescent protein (AAV9-GFP) into each putamen. The post-surgical in-life was restricted to 3 weeks in order to minimize immunotoxicity expected to arise from expression of GFP in antigen-presenting cells. Three main findings emerged from this work. First, the volume over which AAV9 expression was distributed (Ve) was substantially greater than the volume of distribution of MRI signal (Vd). This stands in contrast with Ve/Vd ratio of rAAV2, which is lower under similar conditions. Second, post-mortem analysis revealed expression of GFP in thalamic and cortical neurons as well as dopaminergic neurons projecting from substantia nigra pars compacta, indicating retrograde transport of AAV9. However, fibers in the substantia nigra pars reticulata, a region that receives projections from putamen, also stained for GFP, indicating anterograde transport of AAV9 as well. Finally, one hemisphere received a 10-fold lower dose of vector compared with the contralateral hemisphere (1.5 × 10(13) vg ml(-1)) and we observed a much stronger dose effect on anterograde-linked than on retrograde-linked structures. These data suggest that AAV9 can be axonally transported bi-directionally in the primate brain. This has obvious implications to the clinical developing of therapies for neurological disorders like Huntington's or Alzheimer's diseases.
Insights
Adeno-associated virus serotype 9 (AAV9) demonstrates bidirectional axonal transport in the primate brain, distributing widely beyond the injection site. This finding is crucial for developing gene therapies for neurological disorders.
Area of Science:
- Neuroscience
- Gene Therapy
- Viral Vector Research
Background:
- Adeno-associated virus (AAV) vectors are promising for gene therapy.
- Understanding AAV9's biodistribution and transport in the primate brain is critical for clinical applications.
- Previous studies suggest limited distribution and transport for other AAV serotypes.
Purpose of the Study:
- To investigate the in vivo distribution and axonal transport of adeno-associated virus serotype 9 (AAV9) in the nonhuman primate brain.
- To compare AAV9's distribution volume (Ve) and MRI signal distribution volume (Vd).
- To determine if AAV9 exhibits anterograde and/or retrograde axonal transport.
Main Methods:
- Pilot study involving bilateral parenchymal infusions of AAV9-GFP into the putamen of two Rhesus macaques.
- Short post-surgical in-life period (3 weeks) to minimize immunotoxicity.
- Post-mortem analysis of brain tissue to assess GFP expression and distribution.
Main Results:
- AAV9 expression volume (Ve) was significantly larger than the MRI signal distribution volume (Vd).
- GFP expression was observed in thalamic, cortical, and substantia nigra neurons, indicating retrograde transport.
- GFP was also found in fibers projecting from the putamen to the substantia nigra pars reticulata, indicating anterograde transport.
- A dose-dependent effect was more pronounced for anterograde than retrograde transport.
Conclusions:
- AAV9 is capable of bidirectional axonal transport within the primate brain.
- AAV9 exhibits a wider distribution than previously observed with other AAV serotypes like AAV2.
- These findings support the potential of AAV9 for gene therapy delivery to widespread neural circuits in neurological diseases.
