PhD Scientific Days 2025
Budapest, 7-9 July 2025
Poster Session III. - R: Neurosciences
Genetically targeted, long-term stable and low-immunogenic modulation of brain function: promise or reality?
Name of the presenter
Somogyi Fanni
Institute/workplace of the presenter
HUN-REN Research Centre for Natural Sciences
Authors
Fanni Somogyi1,2, Beatrix Kovács2,3, Klaudia Csikós2,3, Ábel Petik3,4, Domonkos Horváth3,4, Attila B. Dobos3, Lucia Wittner3,5, Dániel Hillier3,4
1: HUN-REN Research Centre for Natural Sciences
2: János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary
3: HUN-REN Research Centre for Natural Sciences, Budapest, Hungary
4: Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
5: Neurology and Neurosurgery, Institute of Mental Health, Budapest, Hungary
Text of the abstract
Whether for circuit dissection or disease modeling: genetic targeting of brain function via transgenic mouse lines has become ubiquitous in experimental neuroscience. In stark contrast, for non-mouse models where a similar diversity of transgenic lines is not available, stable and safe genetically-targeted modulation of brain function remains difficult.
Gene therapy vectors, primarily AAVs, can target cell populations but their long-term efficacy and safety can be hampered by humoral and local immune response as well as by variability of transgene expression. Therefore, genetically-targeted functional access to the brain requires the labeling of a sufficient number of cells at stable transgene expression levels with contained immune response.
Our primary objective has been to identify a delivery route and gene therapy construct that yields optimal transgene expression for long-term optical imaging while also remaining safe in terms of local and systemic immune responses.
We performed long-term optical imaging on 9 animal cohorts across at least 13 weeks each, evaluated the stability of optical activity readout, labelling efficacy, local and systemic immune responses. We found strong nonlinear relationships between dose, expression levels and immune response.
Our work identifies an optimized gene therapy delivery method that enables stable, long-term all-optical imaging in the brain while minimizing immune response.