Baculoviral vectors as a gene therapy tool for gene delivery into astrocytes

GARCIA FALLIT, MATÍAS; PIDRE, MATÍAS LUIS; ASAD, ANTONELA S.; PEÑA AGUDELO, JORGE A.; SAGRIPANTI SOFÍA; NICOLA CANDIA, ALEJANDRO J.; PÉREZ KUPER, MELANIE; MARCHESINI, ABRIL; AMORÓS MORALES, LESLIE C.; GONZALEZ, NAZARENO; ROMANOWSKI, VÍCTOR; SEILICOVICH, ADRIANA; VERA, MARIANA B.; VIDELA-RICHARDSON, GUILLERMO A.; CARUSO, CARLA M.; ZANETTI, FLAVIA A.; CANDOLFI, MARIANELA

Congreso; PRIMER ENCUENTRO DEL CLUB DE LA GLÍA CONO SUR; 2022

SOCIEDAD NEUROLÓGICA ARGENTINA

In search for betterapproaches to treat gliomas we developed baculoviral vectors (BVs) todeliver therapeutic transgenes into these brain tumors. Althoughrecombinant adenoviral (AdV) vectors are the gold standard inneuro-oncology due to their robust transduction efficiency andoptimal safety profile, they are highly immunogenic and virtually theentire general population has pre-existing anti-AdV immunity, whichleads to transient transgene expression. These limitations impairtherapeutic efficacy and have led us to search for alternativetherapeutic vectors. Since BVs are natural pathogens of insects, nopre-existing immunity against BVs has been reported in humans so far,making it a great candidate for gene delivery to the brain. Weevaluated the transduction efficiency and toxicity of BVs in normaland neoplastic astrocytes invitro andin vivoand compared them with those of AdV. Our hypothesis was that BVsconstitute a useful tool for the persistent expression of therapeutictransgenes to treat brain disorders. Therefore, we constructed AdVand BV encoding fluorescent proteins under the control of thecytomegalovirus (CMV) promoter. Using microscopy and flow cytometry,we found that both vectors exert robust transduction efficiency inmurine and human glioma cell lines and short cultures derived frombiopsies, as well as rat and mouse astrocytes. To assess transductionefficiency and neuropathology invivo,vectors were injected by stereotactic surgery into the brain of micewith or without intracranial gliomas. Transduction efficiency wascomparable with both vectors, as it was immune infiltration at theinjection site, with no obvious signs of neurotoxicity. Both vectorsefficiently transduced tumor cells and non-neoplastic astrocytes.Transgene expression was detected 7 and 21 days after injection innaïve brain, and it was lost when mice were preimmunizedsystemically with BVs. Our findings indicate that BVs are excellenttools for transgene delivery in glioma cells and normal astrocytes. p { line-height: 115%; text-align: left; orphans: 2; widows: 2; margin-bottom: 0.25cm; direction: ltr; background: transparent }