AAV vectors trigger neurotoxic DNA damage responses and STING-dependent inflammation in human CNS cells [RNA-seq]

Adeno-associated viral (AAV) vector gene therapy is gaining ground as a treatment option for genetic neurodegenerative diseases tha currently have no cure. Nonetheless, significant toxicity and severe adverse events are emerging in recent clinical trials through mechanisms that remain unclear. We have modelled here AAV-mediated neurotoxicity in the context of the human brain taking advantage of human induced pluripotent stem cell-based technologies. We have used RNA sequencing technologies to interrogate vector-induced cell-intrinsic innate immune mechanisms that could contribute to neurotoxicity in 2D iPSC-derived cultures of atrocytes and neurons respectively. Astrocytes and neurons were differentiated from healty donor iPSCs. At the end of the respective maturation protocols, cells were transduced with the indicated AAV vector serotype or empty capsid controls for 48 hours, and their transcriptomes were compared to those of untreated (UT) controls.