Chemogenetics: drug-controlled gene therapies for neural circuit disorders

Abstract

Many patients with nervous system disorders have considerable unmet clinical needs or suffer debilitating drug side effects. A major limitation of exiting treatment approaches is that traditional small molecule pharmacotherapy lacks sufficient specificity to effectively treat many neurological diseases. Chemogenetics is a new gene therapy technology that targets an engineered receptor to cell types involved in nervous system dysfunction, enabling highly selective drug-controlled neuromodulation. Here, we discuss chemogenetic platforms and considerations for their potential application as human nervous system therapies.

FIGURE 1. Three treatment approaches to nervous system therapy, example of chronic neuropathic pain.

Systemic pharmacotherapy results in widespread distribution of the drug (orange), which modulates (red stars) the affected sensory ganglia as well as all other sensory ganglia, the brain, and other peripheral organs that also express the target for the drug. Surgery procedures permanently disrupt the sensory ganglia (red x’s) to block sensory transmission. Chemogenetics achieves local, tunable, and reversible neuromodulation by targeting a chemogenetic receptor solely to the neuropathic pain-causing ganglia. Ultrapotent chemogenetic receptors use low doses (light yellow) of the chemogenetic drug.

FIGURE 2. DREADD family of chemogenetic receptors.

Receptors based on modifications to the human muscarinic receptors are activated by CNO and have greatly attenuate responsiveness to ACh. hM3Dq activates neurons by inhibiting Kcnq potassium channels. hM4Di inhibits neurons by opening GIRK channels. Other DREADDs, based on modifications of hM3D, engage additional G-protein signaling pathways.

FIGURE 3. PSAM chimeric ion channels.

PSAMs developed from the ligand binding domain (LBD) of the α7 nAChR are spliced to either the IPD of 5HT3 or GlyR to produce chimeric channels for neuron activation or inhibition, respectively. The same PSAM and its cognate agonist (yellow circle) are used for both types of channel. Mutations in the LBD increase drug-potency and reduce ACh sensitivity. PSAM chimeric channels are homomeric pentamers.