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Authors & Affiliations
Oliver Polzer, Ayinde Swildens, Rosa Randoe, Paul J. Lucassen, Evgenia Salta, Carlos P. Fitzsimons
Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by the accumulation of β-amyloid plaques and Tau-containing neurofibrillary tangles, with no effective treatment currently available. To address the complex nature of AD pathology, we investigate a "multiple drugs – multiple targets" approach leveraging miRNA-based therapeutics. miRNAs, short non-coding RNAs, offer unique potential for gene network-based therapies due to their ability to regulate multiple genes within common biological pathways. Dysregulated miR-124 and miR-132, implicated in AD pathology, present promising targets. Here, we present our work on the development of novel cell type-specific AAVs for combined miR-124/miR-132 delivery in the mammalian brain. Building upon preliminary results, ongoing work involves assessing the therapeutic potential of synergistic miR-124/miR-132 delivery in a novel AD mouse model, AppNLGF, at three months of age. Additionally, in vitro assays utilizing a dual fluorescence reporter sensor assay will complement the in vivo studies to evaluate functionality. Our approach provides a versatile toolkit enabling precise cell targeting of miRNA-carrying AAVs in the central nervous system. Through this innovative strategy, we aim to advance the development of effective therapeutics for AD, addressing the urgent need for disease-modifying treatments.