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• W2897329565 abstract "Fibrillar aggregates of tau form the defining pathological hallmarks of Alzheimer's disease (AD), tau variant frontotemporal dementia and tauopathies. Studies of AD, tauopathy and seizure in vivo models have demonstrated therapeutic benefit of reduction of CNS tau levels. We identified an antisense long non-coding RNA gene, MAPT-AS1, overlapping with the 5’ promoter region of the tau gene (MAPT) that potently represses tau levels by influencing ribosomal recruitment of mRNA. Noting the safety of AAV vector-based gene therapy in CNS, we are testing intracranial delivery of MAPT-AS1 transcripts and variants in the htau mouse. The htau mouse model[1] carries full-length human MAPT against a Mapt-/- background and manifests early (∼3m) somatodendritic relocalisation of tau and late (>12m) pathological and behavioural changes reminiscent of AD. We produced AAV9 vectors for CMV promoter-driven expression of a full-length MAPT-AS1 transcript (tNAT1-FL) and a minimised artificial variant as well as an inactive deletion variant (ΔM). Adult htau mice (9-12m) were injected into right hippocampus with AAV9-CMV vectors for tNAT1-FL and ΔM and AAV9-CMV-eGFP as control. Brains harvested 8 weeks later were analysed by Western blot and real-time qRT-PCR. With AAV9-CMV-eGFP, we showed extensive CNS spread of GFP without any site-specific tropism. Eight weeks post-injection, both ipsi- and contralateral sides of htau mice injected with AAV9-CMV with tNAT1-FL showed robust reduction (up to 70%) of tau protein levels that correlate with spread and levels of the tNAT1-FL transcript. In contrast, there were no changes in tau protein levels with expression of ΔM transcript. MAPT-AS1 presents a novel opportunity for therapeutic tau reduction with the advantage of exploiting physiological repression of CNS tau. The excellent safety profile and robust CNS spread and persistence of AAV has made them vector of choice for CNS-targetted gene therapy. The htau mouse model gives us the platform for the pre-clinical study of the benefits of this tau reduction in slowing pathological tau progression and alleviating behavioural deficits displayed by these transgenic mice. [1] Andorfer, C., et al., J Neurochem, 2003. 86:582-90." @default.
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• W2897329565 date "2018-07-01" @default.
• W2897329565 modified "2023-10-16" @default.
• W2897329565 title "P4‐264: A GENE THERAPY APPROACH FOR REDUCTION OF TAU BY TAU LONG NON‐CODING RNA GENE ( <i>MAPT‐AS1</i> ) NATURAL ANTISENSE TRANSCRIPT" @default.
• W2897329565 doi "https://doi.org/10.1016/j.jalz.2018.07.086" @default.
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