Viral Vector Delivery of DREADDs for CNS Therapy

• Published in: Current gene therapy
• Main Authors: Pickering, Ceri A, Mazarakis, Nicholas D
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.01.2021
• Subjects: Viral Vectors; Gene Therapy; AAV; Chemogenetics; CNS; DREADDs; Lentivirus
• ISSN: 1875-5631
• DOI: 10.2174/1566523221666210211102435

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are genetically modified G-protein-coupled receptors (GPCRs), which can be activated by a synthetic ligand that 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. Furthermore, they offer considerable potential for use as a gene therapy strategy 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 to deliver these chemogenetic tools in the literature. This review evaluates each of the prominent strategies currently utilised for DREADD delivery, discussing their respective advantages and limitations. It focuses on Adeno-Associated Virus (AAV)- 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.