Abstract
The present study was designed to characterize transduction of non-human primate brain and spinal cord with AAV5 viral vector after parenchymal delivery. AAV5-CAG-GFP (1 × 1013 vector genomes per milliliter (vg ml−1)) was bilaterally infused either into putamen, thalamus or with the combination left putamen and right thalamus. Robust expression of GFP was seen throughout infusion sites and also in other distal nuclei. Interestingly, thalamic infusion of AAV5 resulted in the transduction of the entire corticospinal axis, indicating transport of AAV5 over long distances. Regardless of site of injection, AAV5 transduced both neurons and astrocytes equally. Our data demonstrate that AAV5 is a very powerful vector for the central nervous system and has potential for treatment of a wide range of neurological pathologies with cortical, subcortical and/or spinal cord affection.
Highlights
Neurological gene therapy development with adeno-associated virus-based vectors (AAV), besides improvements in production methods leading to higher titers of vector, has been marked by three seminal discoveries
Direct infusion of AAV2 into the thalamus resulted in an anterograde transport of vector particles to cortical layers IV and V over a wide territory from prefrontal to occipital cortex[13] and from putamen to substantia nigra pars reticulata (SNpr) in rats and non-human primate (NHP).[14,15]
Direct protein sequence and biochemistry comparison determined that AAV5 serotype is markedly different than AAV2 in terms of capsid conformation.[27]
Summary
Neurological gene therapy development with adeno-associated virus-based vectors (AAV), besides improvements in production methods leading to higher titers of vector, has been marked by three seminal discoveries. This animal showed high GFP expression levels in distal structures (Figure 2e) SNpr, cortex (Figure 2f) and globus pallidus (Figure 2g), structures that project neurons to the thalamus.
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