Volume 68, February 2023, 102329Author links open overlay panelAbstract

Skeletal muscle ion channelopathies are rare genetic diseases mainly characterized by myotonia (muscle stiffness) or periodic paralysis (muscle weakness). Here, we reviewed the available therapeutic options in non-dystrophic myotonias (NDM) and periodic paralyses (PP), which consists essentially in drug repositioning to address stiffness or weakness attacks. Empirical use followed by successful randomized clinical trials eventually led to the orphan drug designation and marketing authorization granting of mexiletine for NDM and dichlorphenamide for PP. Yet, these treatments neither consider the genetic cause of the diseases nor address the individual variability in drug response. Thus, ongoing research aims at the identification of repurposed drugs alternative to mexiletine and dichlorphenamide to allow personalization of treatment. This review highlights how drug repurposing may represent an efficient strategy in rare diseases, allowing reduction of drug development time and costs in a context in which the return on investment may be particularly challenging.

Introduction

Skeletal muscle ion channelopathies are rare genetic diseases caused by mutations in genes encoding ion channels expressed in skeletal muscle [1]. Due to the function of ion channels in skeletal muscle, many mutations alter the excitability of sarcolemma, resulting in muscle stiffness (hyper-excitability) or muscle flaccid weakness (hypo-excitability) (Figure 1). In addition, a severe loss of function of the voltage-gated sodium or calcium channels is associated with congenital myopathy [1].

Due to the extreme rarity of the majority of skeletal muscle ion channelopathies, no targeted pharmacological treatment is available, nor cellular or gene therapies are likely to be developed in a near future due to technical, ethical, and economical issues. There are however two notable exceptions, the non-dystrophic myotonias and the periodic paralyses, for which drugs have been repurposed and recently approved by regulatory agencies.

Section snippetsDrug repurposing in non-dystrophic myotonias

Non-dystrophic myotonia is a neurological rare condition with an estimated prevalence around 1 per 100,000 individuals [2,3]. It is characterized by exacerbated sarcolemma excitability that manifests as delayed relaxation after contraction leading to muscle stiffness. Hyperexcitability is observed on the electromyogram or in muscle fiber intracellular recordings as the so-called myotonic discharges, which is an abnormal run of action potentials. Stiffness can affect various muscles, including

Drug repurposing in periodic paralyses

The periodic paralyses (PPs) are rare neuromuscular disorders characterized by intermittent episodes of flaccid muscle paralysis that can last hours to days, muscle weakness and fatigue [36]. Hyperkalemic PP (HyperPP) and hypokalemic PP type 2 (HypoPP2) are both due to mutations in the SCN4A gene (Figure 1). Mutations in CACNA1S gene encoding the calcium channel Cav1.1 give rise to hypokalaemic PP type 1 (HypoPP1). Andersen-Tawil syndrome (ATS) is caused by mutations in the inward rectifying

Conclusion

The approval of mexiletine and dichlorphenamide for the treatment of NMD and PP, respectively, represent two success of drug repurposing in rare diseases. In both cases, this allowed reintroduction of drugs that had been taken off the local market by manufacturers. In rare diseases, repurposing of drugs should allow to limit the costs related to preclinical and early clinical development phases in a context in which the return on investment may be particularly challenging due to the rarity of

CRediT author contribution statement

Concetta Altamura: Writing, Reviewing and Editing.

Ilaria Saltarella: Writing and Original draft preparation.

Carmen Campanale: Writing and Original draft preparation.

Paola Laghetti. Writing and Original draft preparation.

Jean-François Desaphy: Writing, Reviewing and Editing, Supervision.

Conflict of interest statement

JFD is scientific consultant for Neuroscience Division, Lupin Pharmaceuticals, France (2021/2022).

Acknowledgments

This research received grant from University of Bari (Europe Seeds project “Medineuropa”)

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