BACULOVIRAL VECTORS AS A GENE THERAPY TOOL FOR THE TREATMENT OF BRAIN DISORDERS. Matías Garcia Fallit, Matías L. Pidre, Antonela S. Asad, Jorge A. Peña Agudelo, Sofia Sagripanti, Alejandro J. Nicola Candia, Melanie Pérez Kuper, Abril Marchesini, Leslie C

MATÍAS GARCIA FALLIT; ANTONELA S ASAD; JORGE A. PEÑA AGUDELO; SOFIA SAGRIPANTI; ALEJANDRO J. NICOLA CANDIA; MELANIE PÉREZ KUPER; ABRIL MARCHESINI; LESLIE C. AMORÓS MORALES; NAZARENO GONZALEZ; ADRIANA SEILICOVICH; MARIANA B. VERA; GUILLERMO VIDELA RICHARDSON; FLAVIA ZANETTI; MARIANELA CANDOLFI

Mar del Plata

Otro; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

Sociedad Argentina de Investigación Clínica

Glioblastomas (GBM) are the most frequent and aggressive primary malignant brain tumors in adults for which there are no effective therapeutic alternatives. Recombinant adenoviral (AdV) vectors are the gold standard for gene therapy in neuro-oncology. However, they are highly immunogenic and virtually the entire population has pre-existing anti-AdV immunity, leading to transient transgene expression. Baculoviral (BV) vectors are pathogens of insects, but can also transduce cells from other species. Its advantage is that pre-existing immunity against BV in humans has not been reported so far.In order to develop therapeutic strategies for the treatment of GBM, we evaluated the transduction efficiency of BV as well as its possible neurotoxicity and compared them with those of AdV. Our hypothesis is that BVs constitute a useful tool for the persistent expression of therapeutic transgenes in the brain for the treatment of GBM.We constructed AdV and BV encoding fluorescent proteins under the control of the cytomegalovirus (CMV) promoter. The transduction efficiency of these vectors was evaluated in astrocyte cultures, GBM cell lines and short cultures derived from GBM biopsies by microscopy and flow cytometry. To assess in vivo transduction efficiency and neuropathology, vectors were injected by stereotactic surgery into the brain of naïve and GBM-bearing mice.We observed that even though the transduction efficiency of AdV is higher in rat and mouse cells, both vectors exhibit very similar efficiencies in human GBM cells. Both vectors showed high capacity to transduce normal rat and mouse astrocyte cultures.The transduction efficiency in the brain of naïve mice was comparable with both vectors, as was the immune infiltration at the injection site, with no apparent signs of neurotoxicity. We observed that BV transduce GBM cells and astrocytes in vivo. Brain reporter protein expression was stable for 21 days in naïve mice, but was significantly reduced in mice systemically preimmunized against BV.We conclude that BV may be a useful tool for the expression of therapeutic transgenes in the treatment of GBM