Adeno-associated viral vectors overexpressing neurotrophic factors in hippocampal astrocytes as a potential therapeutic technology for neurodegenerative diseases.

PERALTA F; LÓPEZ HANOTTE J; POSADA JI; BJÖRKLUND T; REGGIANI PC; PARDO J

Buenos Aires

Congreso; XXXVII SAN Annual Congress.; 2022

Sociedad Argentina de Investigación en Neurociencia (SAN).

Neuroinflammation is one of the hallmarks of neurodegenerative diseases (ND) characterized by reactive glial cells that undergo several morphological and transcriptional changes. The most prevalent age-related ND is sporadic Alzheimer's disease (sAD), a condition in which the hippocampus (Hc) is severely affected and where astrocytes have been shown to become reactive, decreasing their neuronal trophic support. In this regard, gene therapy and the use of potent neurotrophic factors, such as Insulin-Like Growth Factor 1 (IGF1) and Glial Cell-Derived Neurotrophic Factor (GDNF), are emerging as promising therapeutic approaches. In a rat sAD model generated by intracerebroventricular (icv) injection of streptozotocin (STZ), we previously studied the morphologic changes of reactive astrocytes. In order to genetically modulate these cells in sAD rats and restore brain homeostasis, we constructed and characterized, in vivo, 3 bicistronic adeno-associated viral vectors that simultaneously overexpress in astrocytes the IGF1, GDNF or GFP genes followed by the TdTomato reporter gene. Vectors were injected in the Hc of adult rats and 3 weeks after injection, we confirmed by RT-qPCR overexpression of the transgenes. By fluorescence and immunohistochemistry, we observed that 97% of transduced cells were astrocytes. Next, we will assess the neuroprotective potential of preventive gene therapy with IGF1 and GDNF in hippocampal astrocytes of icv-STZ treated rats. Reggiani PC y Pardo J: igual participación.