Immunogenicity of Adeno-Associated Virus Serotype 6 in Non-Human Primates
Authors:John Forsayeth, Gregory Heller, Lluis Samaranch, Waldy San Sebastion
Mentor:Krystof Bankiewicz, Professor of Neurological Surgery , University of California, San Francisco
The research group focuses on adeno-associated virus (AAV)-based gene therapy to deliver functional, therapeutic genes to animal models of neurological diseases. Vectors are delivered directly into specific regions of the brain by a real-time MRI-guided system. Previous results had revealed that AAV-serotype 6 directs neuron-specific transduction and is retrogradely transported along neurons in rats. However, in addition to neurons, a small number of astrocytes were transduced. Because astrocytes can present antigen, we investigated the immunogenicity and cell specifity of AAV6 and evaluated its safety as a possible therapeutic candidate. I set out to study the immunogenicity of AAV6 infused directly into the non-human primate putamen. Different markers of immunological response were analyzed by immunohistochemistry. Brain sections from AAV6-treated animals were stained for microglial activation, T cell presence and markers of antigen presentation (MHC-II). The reactivity of these markers and the presence of perivascular infiltration in hematoxylin-eosin staining confirmed an inflammatory response. Immunostaining revealed the presence of T cells in the perivascular cuffs indicating a minor infiltration as well as an incipient reactivity of microglia and up-regulation of antigen-presenting cells. These results suggest the presence of a mild immune response but only localized around the needle track region. However, no indication of a brain-wide immune response or cell death was seen. Although further experiments should be performed, this preliminary data supports AAV6 serotype as a good candidate to be utilized in future clinical trials.