Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are genetically
modified G-protein-coupled receptors (GPCRs), that can be activated by a synthetic ligand which is
otherwise inert at endogenous receptors. DREADDs can be expressed in cells in the central nervous
system (CNS) and subsequently offer the opportunity for remote and reversible silencing or activation
of the target cells when the synthetic ligand is systemically administered. In neuroscience, DREADDs
have thus far shown to be useful tools for several areas of research and offer considerable potential for
the development of gene therapy strategies for neurological disorders. However, in order to design a
DREADD-based gene therapy, it is necessary to first evaluate the viral vector delivery methods utilised
in the literature to deliver these chemogenetic tools. This review evaluates each of the prominent
strategies currently utilised for DREADD delivery, discussing their respective advantages and limitations.
We focus on adeno-associated virus (AAV)-based and lentivirus-based systems, and the manipulation
of these through cell-type specific promoters and pseudotyping. Furthermore, we address how
virally mediated DREADD delivery could be improved in order to make it a viable gene therapy strategy
and thus expand its translational potential.
Keywords: DREADDs, chemogenetics, AAV, lentivirus, gene therapy, CNS, viral vectors.
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