Intracisternal delivery of NFkB-inducible scAAV2/9 reveals locoregional neuroinflammation induced by systemic XXXX treatment.

@entity66 @entity35 @entity4176 @entity9536 @entity4700
We have previously demonstrated disease-dependent gene delivery in the brain using an AAV vector responding to NFkB activation as a probe for inflammatory responses. This vector, injected focally in the parenchyma prior to a systemic @entity4176 (KA) injection mediated inducible transgene expression in the hippocampus but not in the cerebellum, regions, respectively, known to be affected or not by the pathology. However, such a focal approach relies on previous knowledge of the model parameters and does not allow to predict the whole brain response to the disease. Global brain gene delivery would allow to predict the regional distribution of the pathology as well as to deliver therapeutic factors in all affected brain regions. We show that self-complementary @entity4700 /9 (scAAV2/9) delivery in the adult @entity35 cisterna magna allows a widespread but not homogenous transduction of the brain. Indeed, superficial regions, i.e., cortex, hippocampus, and cerebellum were more efficiently transduced than deeper regions, such as striatum, and substantia nigra. These data suggest that viral particles penetration from the cerebrospinal fluid (CSF) into the brain is a limiting factor. Interestingly, @entity4700 /9-2YF a rationally designed capsid mutant (affecting surface tyrosines) increased gene transfer efficiency approximately fivefold. Neurons, astrocytes, and oligodendrocytes, but not microglia, were transduced in varying proportions depending on the brain region and the type of capsid. Finally, after a single intracisternal injection of scAAV2/9-2YF using the NFkB-inducible promoter, KA treatment induced transgene expression in the hippocampus and cortex but not in the cerebellum, corresponding to the expression of the @entity9536 marker of microglial activation. These data support the use of disease-inducible vectors administered in the cisterna magna as a tool to characterize the brain pathology in systemic drug-induced or @entity66 models. However, further improvements are required to enhance viral particles penetration into the brain.
