Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery
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fphar-07-00121 May 7, 2016 Time: 11:45 # 1 REVIEW published: 10 May 2016 doi: 10.3389/fphar.2016.00121 Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery Paola Imbrici1*, Antonella Liantonio1, Giulia M. Camerino1, Michela De Bellis1, Claudia Camerino2, Antonietta Mele1, Arcangela Giustino3, Sabata Pierno1, Annamaria De Luca1, Domenico Tricarico1, Jean-Francois Desaphy3 and Diana Conte1 1 Department of Pharmacy – Drug Sciences, University of Bari “Aldo Moro”, Bari, Italy, 2 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari “Aldo Moro”, Bari, Italy, 3 Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Bari, Italy 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, Edited by: disabling, or life-threatening. In spite of this, ion channels are the primary target of only Maria Cristina D’Adamo, University of Perugia, Italy about 5% of the marketed drugs suggesting their potential in drug discovery. The current Reviewed by: review summarizes the therapeutic management of the principal ion channelopathies Mirko Baruscotti, of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and University of Milano, Italy Adrien Moreau, pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion Institut Neuromyogene – École channels. For most channelopathies the therapy is mainly empirical and symptomatic, Normale Supérieure de Lyon, France often limited by lack of efficacy and tolerability for a significant number of patients. *Correspondence: Other channelopathies can exploit ion channel targeted drugs, such as marketed Paola Imbrici [email protected] sodium channel blockers. Developing new and more specific therapeutic approaches is therefore required. To this aim, a major advancement in the pharmacotherapy of Specialty section: channelopathies has been the discovery that ion channel mutations lead to change This article was submitted to Pharmacology of Ion Channels in biophysics that can in turn specifically modify the sensitivity to drugs: this opens and Channelopathies, the way to a pharmacogenetics strategy, allowing the development of a personalized a section of the journal Frontiers in Pharmacology therapy with increased efficacy and reduced side effects. In addition, the identification Received: 27 February 2016 of disease modifiers in ion channelopathies appears an alternative strategy to discover Accepted: 25 April 2016 novel druggable targets. Published: 10 May 2016 Keywords: ion channels pharmacology, channelopathies, physiopathology, drug discovery and development, Citation: genetics Imbrici P, Liantonio A, Camerino GM, De Bellis M, Camerino C, Mele A, Giustino A, Pierno S, De Luca A, INTRODUCTION Tricarico D, Desaphy J-F and Conte D (2016) Therapeutic Approaches Ion channels are membrane proteins that selectively regulate ion fluxes across the membranes of to Genetic Ion Channelopathies and Perspectives in Drug Discovery. cells and cellular organelles, their gating mechanism depending on changes in membrane voltage, Front. Pharmacol. 7:121. ligand binding or physical and chemical stimuli. The presence of distinct ion channel isoforms doi: 10.3389/fphar.2016.00121 and their age-dependent and tissue-specific expression allow the fine regulation of many cellular Frontiers in Pharmacology | www.frontiersin.org 1 May 2016 | Volume 7 | Article 121 fphar-07-00121 May 7, 2016 Time: 11:45 # 2 Imbrici et al. Pharmacotherapy of Ion Channelopathies functions, such as cell excitability, contraction, neurotransmitter have been successfully employed for decades as anticonvulsants, and hormone release, gene expression, ion and water homeostasis antiarrhythmics, and local anesthetics (Catterall and Swanson, (Hibino et al., 2010; Jan and Jan, 2012; Catterall and Swanson, 2015). Great interest is emerging from the possibility to develop 2015; Jentsch, 2015; Zamponi et al., 2015). sodium channel inhibitors for the treatment of neuropathic pain Given the pivotal roles played by ion channels and their and to repurpose marketed blockers for other medical indications extensive distribution, it is not surprising that mutations in (Desaphy et al., 2013a, 2014; Matthews and Hanna, 2014; de ion channels genes, or their interacting proteins, cause specific Lera Ruiz and Kraus, 2015). KCNQ openers have been placed inherited ion channelopathies, ranging from relatively common in clinics for their anticonvulsant effects (Humphries and Dart, ones, such as idiopathic epilepsies, to very rare diseases 2015) and KATP channels are promptly targeted by sulfonylureas (Figure 1). Despite the differences in their genetic origin in neonatal diabetes (De Franco et al., 2015). Calcium channels and clinical setting, ion channelopathies share some common blockers are widely used as symptomatic antiarrhythmics. features regarding pathophysiology and therapeutic approach. Conversely, chloride channels represent a relatively under- In general, loss- or gain-of-function mutations translate into explored target class for drug discovery (Verkman and Galietta, a principal “organ-specific” clinical phenotype (Cannon, 2015; 2009; Imbrici et al., 2015a; Jentsch, 2015). Unfortunately, Spillane et al., 2016). The clinical manifestation of the disease several drugs targeting ion channels, such as sodium channel depends on the type of mutation and functional consequences modulators, are not able to discriminate among ion channel on channel activity, the cellular and subcellular localization isoforms, hence at risk of causing unwanted side effects (Catterall, of the channel isoform, and the channel oligomeric assembly 2014; Grunnet et al., 2014). With a few exceptions, much-needed (Kullmann and Waxmann, 2010). Since first discovery, the specific ion channels modulators are lacking. clinical spectrum of most channelopathies has broadened as Therefore, to guarantee patients suffering from channel- new carrier families and new mutations have been identified. opathies a personalized therapy, novel molecules are under In some cases, the range of symptoms associated with specific development and pharmacological strategies have been channelopathies are not easily explained at a molecular and explored to identify novel drug targets. In principle, the functional level and, besides the disease-causing mutation in better understanding of the genetic and functional defects a particular ion channel gene, they might stem from the underlying channelopathies will allow to deliver patients a interplay of different genes and life conditions acting as precision medicine specifically targeting the biological effects of disease modifiers (Kullmann and Waxmann, 2010; Kearney, the disease-causing mutation, such as a biophysical or folding 2011; Furby et al., 2014; Swaggart and McNally, 2014; Portaro defect. Drug design and development are being greatly assisted et al., 2015). Other channelopathies are further complicated by by the recently identified crystal structures of several ion comorbidity, including seizures, myotonia, neurodevelopmental channels, by computer modeling, by high-throughput screening delay, arrhythmias, or diabetes that led to the definition of methods, by novel genetic studies and, finally, by transgenic multiorgan syndromes. As a consequence of such genetic and and pharmacologically induced cell and animal models of clinical complexity and of the rarity of affected patients, a channelopathies (Feng et al., 2010; Hibino et al., 2010; Jan precise diagnosis for several channelopathies is still difficult and Jan, 2012; Tikhonov and Zhorov, 2012; Pa¸sca et al., 2014; to be made and a genotype-phenotype correlation cannot Jentsch, 2015; Rubinstein et al., 2015; Zamponi et al., 2015; Zou, be easily defined. This, in turn, can subtsantially affect the 2015). Here we summarize the main pharmacological strategies choice of the most appropriate therapeutic management. The performed to treat major channelopathies caused by mutations in elevated cost of drug discovery restrains the development of voltage-gated and inward rectifying ion channels. Although, the new drugs for these rare diseases that are generally neglected involvement of other classes of ion channels and transporters, by pharmaceutical companies. Furthermore, as patients’ groups including neurotransmitter-gated channels (Spillane et al., are very small, clinical trials of statistical significance are 2016), cyclic nucleotide-gated channels, volume-regulated and difficult to run. A few channelopathies, such as sodium calcium-activated anion channels (Hoffmann et al., 2015) is also channel myotonias (SCMs) or neonatal diabetes, may benefit well-established in channelopathies, these are not detailed in this from a targeted pharmacotherapy (Desaphy et al., 2013b; review. Finally, although rare, some channelopathies may serve De Franco et al., 2015). In some cases, a pharmacogenetic as a useful paradigm