A Review of Current and Prospective Treatments for Channelopathies, with a Focus on Gene and Protein Therapy.

Reduced cell surface expression or the malfunctioning of ion channels gives rise to a group of disorders known as channelopathies. To treat the underlying cause, the delivery and/or expression of a functional ion channel into the cell membrane of the cell of interest is required. Unfortunately, for most channelopathies, current treatment options are only symptomatic and treatments that rectify the underlying damage are still lacking. Within this context, approaches that rely on gene and protein therapy are required. Gene therapy would allow the expression of a functional protein, provided that the cellular machinery in the diseased cell could correctly fold and traffic the protein to the cell membrane. Whereas protein therapy would allow the direct delivery of a functional protein, provided that the purification process does not affect protein function and a suitable delivery vehicle for targeted delivery is used. In this review, we provide an overview of channelopathies and available symptomatic treatments. The current state of gene therapy approaches mainly using viral vectors is discussed, which is followed by the role of nanomedicine in protein therapy and how nanomedicine could be exploited for the delivery of functional ion channels to diseased cells.

Delivery of trans-membrane proteins by liposomes; the effect of liposome size and formulation technique on the efficiency of protein delivery.

Channelopathies are disorders caused by reduced expression or impaired function of ion channels. Most current therapies rely on symptomatic treatment without addressing the underlying cause. We have recently established proof of principle for delivery of functional ion channel protein into the membrane of target cells using fusogenic liposomes incorporating glycine receptor (GlyR)-containing cell membrane fragments (CMF) that were formulated by thin film hydration. Here, the effect of liposome size and the formulation technique on the performance of the delivery vehicle was assessed. Three types of liposomes were prepared using lecithin and cholesterol, (i) small (SL), and (ii) large (LL) liposomes made by thin film hydration, and (iii) small liposomes prepared by vortex agitation (V-SL). All liposomes were evaluated for their ability to (i) incorporate GlyR-rich CMF, (ii) fuse with the cell membrane of target cells and (iii) deliver functional GlyR, as assessed by patch-clamp electrophysiology. SL prepared by thin film hydration offered the most effective delivery of glycine receptors that gave clear glycine-mediated currents in target cells. LL showed higher incorporation of CMF, but did not effectively fuse with the target cell membrane, while V-SL did not incorporate sufficient amounts of CMF. Additionally, SL showed minimalin vivotoxicity upon intrathecal injection in mice. Thus, liposome-mediated delivery of membrane proteins may be a promising therapeutic approach for the treatment of channelopathies.