Synergetic microRNA delivery for therapeutic targeting in Alzheimer’s disease

Abstract Background Alzheimer’s disease (AD) is a complex multigenic disorder primarily defined by the presence of β‐amyloid‐containing plaques and Tau‐containing neurofibrillary tangles. To date, there is no available treatment and the failure of numerous single‐target clinical trials shifts more and more the focus to ‘multiple drugs – multiple targets’ pharmacological approaches. miRNAs are short non‐coding RNAs that control the expression of specific target genes, often within the same biological pathways. This makes miRNA‐based therapeutics uniquely suited for gene network‐based approaches, as they may regulate common sensitive hubs in biological pathways relevant for AD. Importantly, most gene transcripts are regulated by multiple miRNAs, leading to functional convergence and increased regulatory strength and accuracy. miR‐124 and miR‐132 are among the miRNAs dysregulated in human AD brain and may counteract AD pathology and memory deficits via common pathways in rodent models of AD. Here, we directly address the therapeutic potential of synergistic miR‐124/miR‐132 delivery in AD. Method We first evaluate the in vitro efficiency of miRNA‐carrying pAAV plasmids to overexpress mature miRNAs individually or combined using transfection in HEK293T cells. Second, delivery of the generated AAVs via stereotactic surgery is employed to assess their efficiency in vivo. Result Here we show preliminary data on the development of cell type‐specific AAVs for the combined delivery of two miRNAs, namely miR‐124 and miR‐132, in the mammalian brain. We demonstrate their efficiency in vitro as well as in vivo to label targeted cells and sufficiently increase miRNA levels. Conclusion Our approach provides a distinctive toolkit to enable precise cell targeting, dosing and toxicity control of a combinatorial miRNA carrying AAV system in the central nervous system.