Biodistribution of AAV-TT and AAV9 in the Nonhuman Primate Brain

The adeno-associated virus (AAV) capsid variant known as “true type” (AAV-TT) is a capsid with enhanced central nervous system tropism and efficient retrograde transport across brain circuits. This property enables AAV-TT to transduce neurons in multiple regions projecting to the site of injection, as previously shown in rodent and sheep models. Such spreading offers the potential for broad therapeutic vector distribution to functionally connected brain areas via a single intraparenchymal administration. To assess the clinical potential of AAV-TT, we delivered a green fluorescent protein (GFP)-expressing AAV-TT vector into the left commissural putamen of two young adult Macaca fascicularis . For comparison, two additional animals received AAV9-GFP. Four weeks post-injection, animals were euthanized, and whole-brain transduction patterns were analyzed using a dedicated Aiforia ® deep learning-based image analysis algorithm to quantify GFP+ neurons. We observed GFP expression in structures known to innervate the injection site, consistent with retrograde transport. Both AAV-TT and AAV9 showed similar overall distribution patterns, but AAV-TT demonstrated modestly enhanced neuronal transduction efficiency compared with AAV9. This study provides the first direct comparison of AAV-TT and AAV9 in the adult nonhuman primate brain and positions AAV-TT as a promising tool for disease modeling and therapeutic interventions in neurodegenerative disorders targeting anatomically distributed neural circuits.