AAV6 Preferentially Transduces Human Choroid Plexus Epithelium in Cerebrospinal Fluid

Adeno-associated virus (AAV) vectors for gene delivery have demonstrated efficacy in treating genetic and acquired human diseases. For the treatment of neurological disorders, AAV delivery via the cerebrospinal fluid (CSF) enables transduction of therapeutic genes to cellular targets in the nervous system, bypassing bloodstream barriers, greatly reducing the viral dose, and minimizing systemic toxicity, compared with intravenous AAV administration. The choroid plexus (ChP) regulates CSF composition and represents a compelling, predominantly nonneural target for the sustained delivery of therapeutic molecules. ChP-specific transduction by AAV delivery within the CSF has been characterized in animal models, but the tropism for human ChP has not been evaluated due to limited accessibility of live tissue. Here, using an ex vivo assay, we ranked AAV1, AAV4, AAV5, AAV6, and AAV9 capsids (each with recombinant AAV2 genomes encoding green fluorescent protein) according to their relative tropism for surgically resected human ChP tissue incubated in allogeneic human CSF. Among the tested capsid serotypes, AAV6 exhibited the highest transduction of human ChP epithelial cells, which was dependent on both the dose and duration of AAV exposure. AAV6 showed relatively low transduction of neocortical and leptomeningeal tissue. These findings provide a human tissue benchmark for capsid selection and inform further preclinical development of ChP-targeted therapies.