Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery

Abstract

In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, disabling, or life-threatening. In spite of this, ion channels are the primary target of only about 5% of the marketed drugs suggesting their potential in drug discovery. The current review summarizes the therapeutic management of the principal ion channelopathies of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion channels. For most channelopathies the therapy is mainly empirical and symptomatic, often limited by lack of efficacy and tolerability for a significant number of patients. Other channelopathies can exploit ion channel targeted drugs, such as marketed sodium channel blockers. Developing new and more specific therapeutic approaches is therefore required. To this aim, a major advancement in the pharmacotherapy of channelopathies has been the discovery that ion channel mutations lead to change in biophysics that can in turn specifically modify the sensitivity to drugs: this opens the way to a pharmacogenetics strategy, allowing the development of a personalized therapy with increased efficacy and reduced side effects. In addition, the identification of disease modifiers in ion channelopathies appears an alternative strategy to discover novel druggable targets.

Keywords: channelopathies; drug discovery and development; genetics; ion channels pharmacology; physiopathology.

FIGURE 1

Schematic diagram illustrating the main inherited ion channelopathies of CNS, PNS, skeletal muscle, heart, kidney, pancreas, and bone.

FIGURE 2

Pharmacogenetics of myotonic sodium channel mutants. (A,B) Representative sodium current traces from hNav1.4 WT channels and myotonic G1306E mutants recorded in transfected cells at steady-state before and during application of mexiletine at 0.1 and 10 Hz stimulation frequencies. (C) Concentration-effect relationships for mexiletine on WT and G1306E, fitted to a first-order binding function. (D,E) Effects of flecainide on sodium currents in the same conditions as in (A,B). (F) Concentration-effect relationships for flecainide on WT and G1306E. The G1306E mutation impairs mexiletine inhibition, while leaving flecainide affinity unchanged. Consequently, patients carrying G1306E, who suffer form a severe form of myotonia, obtained significant improvement by shifting treatment from mexiletine to flecainide.

FIGURE 3

Electrophysiological drug testing on expressed chloride channels and docking simulation. (A) Representative CLC-Ka patch-clamp recordings from transfected HEK293 cells, before and after the application of a synthetic compound, SRA-36. (B) Dose-response curve of CLC-Ka current inhibition by SRA-36 measured at +60 mV. (C) Model of the SRA-36 top-scored docking pose resulting from Induced Fit Docking simulations using a homology model of ClC-Ka modeled on the crystal structure of ClC-ec1.

FIGURE 4

Schematic diagram illustrating the process of drug discovery, from the analysis of disease pathophysiology to development of a precision medicine.