AAV vectors trigger DNA damage response-dependent pro-inflammatory signalling in human iPSC-derived CNS models and mouse brain

Helena Costa-Verdera, Vasco Meneghini, Zachary Fitzpatrick, Monah Abou Alezz, Emily Fabyanic, Xin Huang, Yulia Dzhashiashvili, Avantika Ahiya, Elisabeth Mangiameli, Erika Valeri, Giovanni Crivicich, Silvia Piccolo, Ivan Cuccovillo, Roberta Caccia, Ying Kai Chan, Bérangère Bertin, Giuseppe Ronzitti, Esteban A. Engel, Ivan Merelli, Federico Mingozzi, Angela Gritti, Klaudia Kuranda and Anna Kajaste-Rudnitski ()
Additional contact information
Helena Costa-Verdera: IRCCS San Raffaele Scientific Institute
Vasco Meneghini: IRCCS San Raffaele Scientific Institute
Zachary Fitzpatrick: Inc.
Monah Abou Alezz: IRCCS San Raffaele Scientific Institute
Emily Fabyanic: Inc.
Xin Huang: Inc.
Yulia Dzhashiashvili: Inc.
Avantika Ahiya: Inc.
Elisabeth Mangiameli: IRCCS San Raffaele Scientific Institute
Erika Valeri: IRCCS San Raffaele Scientific Institute
Giovanni Crivicich: IRCCS San Raffaele Scientific Institute
Silvia Piccolo: IRCCS San Raffaele Scientific Institute
Ivan Cuccovillo: IRCCS San Raffaele Scientific Institute
Roberta Caccia: IRCCS San Raffaele Scientific Institute
Ying Kai Chan: Harvard University
Bérangère Bertin: Genethon
Giuseppe Ronzitti: Genethon
Esteban A. Engel: Inc.
Ivan Merelli: IRCCS San Raffaele Scientific Institute
Federico Mingozzi: Inc.
Angela Gritti: IRCCS San Raffaele Scientific Institute
Klaudia Kuranda: Inc.
Anna Kajaste-Rudnitski: IRCCS San Raffaele Scientific Institute

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Adeno-associated viral (AAV) vector-based gene therapy is gaining foothold as treatment for genetic neurological diseases with encouraging clinical results. Nonetheless, dose-dependent adverse events have emerged in recent clinical trials through mechanisms that remain unclear. We have modelled here the impact of AAV transduction in cell models of the human central nervous system (CNS), taking advantage of induced pluripotent stem cells. Our work uncovers vector-induced innate immune mechanisms that contribute to cell death. While empty AAV capsids were well tolerated, the AAV genome triggered p53-dependent DNA damage responses across CNS cell types followed by the induction of inflammatory responses. In addition, transgene expression led to MAVS-dependent activation of type I interferon responses. Formation of DNA damage foci in neurons and gliosis were confirmed in murine striatum upon intraparenchymal AAV injection. Transduction-induced cell death and gliosis could be prevented by inhibiting p53 or by acting downstream on STING- or IL-1R-mediated responses. Together, our work identifies innate immune mechanisms of vector sensing in the CNS that can potentially contribute to AAV-associated neurotoxicity.

Date: 2025
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DOI: 10.1038/s41467-025-58778-3

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