Neurons were the big players in neuroscience research until recent efforts identified that astrocytes too are active players in brain function. Astrocytes are the most abundant type of non-neuronal cells in the brain. In addition to being essential supporters of neuronal function, they play an active role in brain function by the uptake and release of neurotransmitters through the tripartite synapse. Astrocytes play a crucial role in the maintenance of the health and function of the central nervous system and thus astrocytic dysfunction has been implicated in many neurological diseases. Hence, the delivery of small molecule drugs specifically to astrocytes in coordination with gene therapy is a potential therapeutic tool to activate the expression of therapeutic genes to re-establish healthy astrocytic functions. Recently, a targeting moiety was developed in our group that facilitates the delivery of diverse small molecule cargo to astrocytes. Here we utilize this targeting moiety to explore its use as an astrocyte specific drug delivery platform to manipulate astrocytes. We focus on delivering the drug tamoxifen, which is widely used to control gene expression in rodents. Since tamoxifen does not have a potential site of modification to attach the tag while retaining the activity of the molecule, we explored a traceless delivery strategy. The active metabolite 4-hydroxytamoxifen will be caged with a linker attached to the targeting moiety. After delivery of the molecule to astrocytes, the active drug will be released in the presence of light. The traceless targeted delivery strategy will help us to evaluate the ability of the targeting moiety to deliver drugs to astrocytes and to explore the release of different drug candidates in the native form inside astrocytes. Additionally, the tamoxifen-inducible Cre-ER/loxP system will open the door to manipulate astrocytes through controlled gene expression of specific genes in astrocytes. In the future, the molecules we describe have potential use in gene therapy applications for exploring therapeutic aspects of astrocytes in various neurological diseases.

Controllable gene expression in astrocytes using cell-specific delivery of 4-hydroxytamoxifen

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